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CN87103225A - Antidepressant non-calcium cyclic AMP (CAMP) phosphodiesterase inhibitors - Google Patents

Antidepressant non-calcium cyclic AMP (CAMP) phosphodiesterase inhibitors Download PDF

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CN87103225A
CN87103225A CN87103225.2A CN87103225A CN87103225A CN 87103225 A CN87103225 A CN 87103225A CN 87103225 A CN87103225 A CN 87103225A CN 87103225 A CN87103225 A CN 87103225A
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cdcl
base oxygen
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CN1018827B (en
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尼古拉斯·亚历克斯·萨科曼诺
弗雷德里克·詹姆斯·维尼克
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Pfizer Corp SRL
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/72—Two oxygen atoms, e.g. hydantoin
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Abstract

Antidepressive with (I) formula, R in the formula 1It is multi-ring alkyl; R 2Be methyl or ethyl, X is O or NH, and Y comprises 5-or the 6-unit heterocycle with 1 or 2 nitrogen-atoms; Or have add up to 3 nitrogen-atoms (each the ring on have a nitrogen-atoms and two rings to have an angle nitrogen-atoms) the condensed-bicyclic heterocycle.

Description

Antidepressant calcium independent cyclic amp (CAMP) phosphodiesterase inhibitor
The present invention relates to have the antidepressive that following formula is represented:
Figure 87103225_IMG16
R in the formula 1It is poly-cycloalkyl; R 2Be that methyl or ethyl and Y are saturated or undersaturated 5 or 6 Yuans nitrogen heterocyclic rings or the condensed-bicyclic heterocycle with 3 nitrogen-atoms.More particularly, the present invention is relevant such compound, and wherein Y is 5-or 6 element heterocycles with one or 2 nitrogen-atoms; Or on each ring, there are a nitrogen-atoms and two rings to have the condensed-bicyclic heterocycle of an angle nitrogen-atoms.
United States Patent (USP) 4,012,495 and 4,193, a series of poly-alkoxyl phenyls of 4-(with formula (A) have been narrated in No. 926 and part continuation application)-2-Pyrrolidone:
Figure 87103225_IMG17
R in the formula 1And R 2Be until the alkyl of 18 carbon atoms or substituent arbitrarily (C to be arranged 1-5) alkyl; R 3Be H or OCH 3; R 4Be H, alkyl, aryl or acyl group, reaching X is O or S, this compounds has psychotolytic activity.Hydroxyl R 1And R 2Examples of groups especially, cycloalkyl and cycloalkyl alkane, preferably 3 to 7 carbon atoms.At United States Patent (USP) 4,153, those 1-positions on its pyrrolidone ring of having narrated relevant formula (A) in No. 713 have-C(O) compound that replaces of R group, can be used as major tranquilizer, and wherein R is alkyl, aryl, aralkyl, the amino or amino that replaces.
Similar compound series with general formula (B):
Figure 87103225_IMG18
R in the formula 1And R 2Definition and above-mentioned general formula (A) in identical; R 3Be hydrogen, any substituent alkyl is arranged, alkenyl, aryl, aralkyl or acyl group; R 4And R 5Can be hydrogen, and X is O or S, this be in English Patent 1,588, is described in No. 639.These compounds are concluded to have the depressed effect of maincenter, the effect of anti-Dopamine HCL sample, evil and the anticonvulsant effect of anti-impression, and have certain neuroleptic effect that is similar to.
United States Patent (USP) 4,308 has disclosed for No. 278 and to have had the compound that subtracts the active relevant general formula (C) of appetite.
Figure 87103225_IMG19
R in the formula 1Be (C 3-6) cycloalkyl or benzyl; Or individual R 2And R 3Be hydrogen or (C 1-4) alkyl; R 4Be R 2Or carbalkoxy; And R 5Be hydrogen or carbalkoxy.United States Patent (USP) and division 3,636,039 and 3,923 thereof, No. 833 and divide an application, the benzyl imidazole ketone that has disclosed general formula (D) can be used as the hypertension agent.
Figure 87103225_IMG20
R in the formula 1-R 4Be selected from the various groups that comprise hydrogen and lower alkoxy.
At United States Patent (USP) 4,261, narrated in No. 995 from suitable phenyl aldehyde by intermediate trimethylene cyanide and glutaramide derivative, prepare hypotensive agent 1,4,5, the 6-tetrahydropyrimidine.
Antidepressive of the present invention has logical formula I
Figure 87103225_IMG21
R in the formula 1It is the multi-ring alkyl of from 7 to 11 carbon atoms;
R 2Be methyl or ethyl;
X is O or NH; With
Y comprises one 5 or 6 element heterocycles, especially one has the saturated of 1 or 2 nitrogen-atoms or undersaturated 5 or 6 element heterocycles, have on the described ring can select arbitrarily to replace=O or=S, if when said optional group be exist and heterocycle on when a nitrogen-atoms is arranged, then this optional group is to be positioned on the carbon atom adjacent with said nitrogen-atoms, if having on heterocycle is 1 each other, during two nitrogen-atoms of 3, then said optional group is to be positioned on two carbon atoms between the nitrogen-atoms; Those have on the heterocyclic nitrogen atom of a hydrogen atom, have to select (the C that replaces arbitrarily 1-5) alkyl, (C 2-5) alkenyl, (C 1-5) silane alcohol base, benzyl, styroyl or benzoyl; 1,2,3-thia diazo 2, the 2-dioxide (has on the nitrogen-atoms wherein and can select (the C that replaces arbitrarily 1-5) alkyl, (C 2-5) alkenyl, (C 1-5) silane alcohol base, benzyl, styroyl or benzoyl; The bicyclic heterocycle part contains 3 nitrogen-atoms altogether, and wherein each ring has a nitrogen-atoms, and another nitrogen-atoms (angle nitrogen-atoms) then is that two rings are common.
The present invention also comprises the pharmaceutically acceptable acid salt with the logical formula I compound of a basic nitrogen atom.In addition, the pharmaceutical composition of logical formula I is also included within the scope of the present invention with their purposes as antidepressive.And the logical formula I compound of preparation and the method for intermediate thereof and new intermediate are also included among the present invention.Some the ring in (R) groups and heterocycle (Y) part at The compounds of this invention exists three-dimensional center more, and this can recognize for those skilled in the art.Racemization one non-enantiomer mixture and one optically-active are led the structure body and are also included among the present invention.
Some compounds that this paper narrated are parts of the present invention, and they are specially adapted to the intermediate as the logical formula I compound of preparation.Logical formula IV is hereinafter arranged, (V), (VII), (VIII), (IX), (XI), (XII), (X III), the compound of (X IV) and (X VI).With regard to the compound of general formula (XI) and (XII), the tautomeric form of said compound comprises in the present invention, even have only a kind of alkene shape to represent with described general formula.
The characteristics of logical formula I compound are to have the good curing index, and resemble 4-(3-(encircles penta oxygen)-4-p-methoxy-phenyl than compound known)-2-Pyrrolidone has the emetic phenomenon of obvious minimizing, this is at United States Patent (USP) 4,193, be described in No. 926, its generic name is rolipram.
More particularly, the present invention relates to logical formula I compound, Y is in the formula:
Figure 87103225_IMG22
Figure 87103225_IMG23
And R 1, R 2Identical with the definition of X and above-mentioned generalformula; R 3Be hydrogen (C 1-5) alkyl, (C 2-5) alkenyl, benzyl or styroyl, and R 4Be hydrogen (C 1-5) alkyl, (C 1-5) silane alcohol base, have a basic group or benzoyl with choosing at random.
R is (C 7-10) example of multi-ring alkyl has:
Dicyclo (2.2.1) heptyl
Dicyclo (2.2.1) octyl group
Dicyclo (3.2.1) octyl group
Three ring (3.2.1.0 2,6) decyl
Three ring (3.3.1.1 3,7) decyl-
2, the 3-indanyl
The R that is suitable for 1Group is:
Dicyclo (2.2.1) heptan-2-base
Dicyclo (2.2.1) suffering-2-base
Dicyclo (3.2.1) oct-3-yl
Three ring (3.2.1.0 2,6) last of the ten Heavenly stems-the 4-base
Three ring (3.3.1.0 2,6) last of the ten Heavenly stems-the 8-base
Three ring (3.3.1.1 3,7) last of the ten Heavenly stems-the 2-base-
1,2-indane-2-base
Preferential R 1Group be dicyclo (2.2.1)-heptan-2-base and 2,3-indane-2-base.
For above-mentioned classes of compounds, the X group is O and R 2When being methyl, these compounds are compound preferably normally.
For a given R 1Group, suitable Y group are 5-element heterocycle, bicyclic heterocycle and saturated 6-person's heterocyclic ring systems.Y group is saturated 5-and 6-element heterocycle system and bicyclic heterocyclic system (above-mentioned loop systems (a)-(d), (g), (l) and (m)-(p)) preferably.Good especially is heteroaryl ring system (a), (g), (l) and (m)-(p).
According to the biological activity viewpoint, the outer isomer of a given logical formula I compound is owing to there is bigger potential, thereby generally is suitable for than interior allosome.In actual practice, just the formula I compound of asymmetric center is arranged on different R and/or Y, the mixture of isomers of a given logical formula I compound normally is suitable for, because the preparation mixture is easier than pure isomer.
The product of the logical formula I of the present invention (wherein X is that O and Y represents heterocycle (a) and (b) or (c)) is that follow procedure A prepares:
Figure 87103225_IMG24
In program A, (II) is converted into (III) and synthesizes with Williamson and finish, comprising replacing with the hot nuclear of phenates ionic replacement fontanelle compound ionic.Known method be included in reaction-inert solvent by with alkali, for example reaction carried out of metal hydroxides or carbonate is converted into the phenates ion with phenol reagent (II).With reaction-inert solvent, its meaning is meant that this solvent can not react with starting raw material, intermediate or product, and the productive rate that is unlikely desired product plays adverse influence.Suitable solvent is a dimethyl formamide, tetrahydrofuran (THF), dioxan and two (2-methoxy ethyl) ether.Suitable R fontanelle compound, preferably R ' Br or R ' Cl, as up to about 150 ℃, with the phenates ionic reaction, mixed ether (III) then separates by known working method at high temperature.In this reaction, with the outer or internal (position) isomer of multi-ring alkyl fontanelle compound, can produce the isomer mixture of corresponding ether (III), if need, can be by known step such as chromatography method with this mixture separation.
In addition, the mixture ether of formula III can be in the presence of as the triphenylphosphine-azodicarboxy diethyl ester of the activator of the hydroxyl that participates in reaction, by suitable polynaphthene alcohol (R '-OH) and phenol (II) react and prepare.Be reflected at reaction-inert solvent,, at room temperature the diethylazodicarboxylate added in the tetrahydrofuran solution of polynaphthene alcohol, phenol and triphenylphosphine usually as carrying out in the tetrahydrofuran (THF) (THF).After adding, reaction is back to substantially finishes, and mixed ether is separated with known working method.
In addition, their available suitable multi-ring alkyl ketone and a little tea phenol has in the presence of right-toluenesulphonic acids in alkane solvent neutralization to react, and is removing generation multi-ring alkyl ketal under the condition of byproduct water.Ketal is through lithium aluminum hydride/AlCl 3Reduction obtains 2-polynaphthene oxygen base phenol, then its bromination is obtained 4-bromo-(2-polynaphthene oxygen base)-phenol, and then it is changed into OR on phenolic group 2Ether.The metalepsy that replaces bromo functional groups with formyl radical be with it in tetrahydrofuran (THF), handle and then with using N, the dinethylformamide quenching is finished with tetrabutyl lithium.All above-mentioned reactions are all undertaken by the known operation method.Other starting raw material required for the present invention, if be not easy to obtain, or what be not described in the art in the past, all available those known working method described herein prepare.
The amino-nitrile of logical formula IV or cyano group amine can synthesize by Strecker and prepare, comprising the ketonic oxygen of using amino or the amino that replaces and cyano group to replace formula III.This working method reacts in reaction-inert solvent such as ethanol when comprising aldehyde (III) and suitable amine (or ammonia) with the form of its hydrochloric acid and sodium cyanide tool.Reaction is carried out at ambient temperature, and good yield is arranged, and the available known method of product (IV) is separated.
General formula (V) compound can obtain by reducing logical formula IV compound.As everyone knows, the reductive action that nitrile is reduced into amine can be by comprising the various methods such as shortening with precious metal or Raney's nickel catalyst, by using such as lithium aluminum hydride, diisobutylaluminium hydride, hydride such as two (2-methoxy ethoxy) the aluminium sodium of diisobutylaluminium hydride sodium and hydrogenation carry out.The reductive agent of Shi Yonging is a diisobutylaluminium hydride in the present invention, (being called DiBal-H).Reductive action can be undertaken by the solution of cyano group amine aqueous solution (IV) in reaction-inert solvent such as toluene, hexanaphthene, ether, tetrahydrofuran (THF), heptane, hexane and methylene dichloride is added the solution of DiBal-H in reaction-inert solvent (preferably using the same solvent used with cyano group amine) easily.In that cyano group amine is added in the process of reductive agent, be reflected at low temperature and carry out as being lower than under-50 ℃, also need to carry out again 2-4 hour.Slowly be warming up to about 0 ℃ then, destroy excessive reductive agent, product separates with standard method.
By (V) cyclisation is the (cyclic action of I-a), it wherein is 2-imidazolinedione-5-base group, it be with diamines (V) in reaction-inert solvent, use N, N '-carbonyl dimidazoles or 1,1-carbonyl diurethane-1,2, the 4-triazole handles obtaining under 20 °-65 ℃ in four furans or tetrahydrofuran (THF)-benzene.Can use phosgene, but because it is bigger than the above-mentioned cyclizing agent toxicity of mentioning, and need high temperature, so it should not be used for cyclisation.General formula (the corresponding thioketones of I-b), wherein Y is 2-imidazolidyl-5-base group, can prepare with similar approach, but use N, N '-thio-carbonyldiimidazole is made cyclizing agent.General formula (compound of I-C) is that middle Y is 1,2,3-thiadiazine-5-base 2, and the 2-dioxide is by preparing as cyclizing agent with sulphonamide.Be reflected in the pyridine and carry out under reflux temperature, finish until reaction, product separates with currently known methods.
Logical formula I compound, wherein Y is a heterocyclic ring (f) and X is O, can come according to program B
Preparation:
Figure 87103225_IMG25
Logical formula VI reactant can be prepared by logical formula III compound with the known method in present technique field.Suitable method comprises that logical formula III carries out oxidation with the method for Jones reagent (chromic acid and sulfuric acid are in water).In phenyl aldehyde reactant (III) lining of adding under the envrionment temperature in acetone, acid (VI) separates with standard method with oxygenant.If required, acid (VI) can be passed through the further esterification of currently known methods, obtains lower alkyl esters, preferably methyl esters.Then ester and about two normal sulfinyl sodium methylate (being to form by sodium hydride and methyl-sulphoxide reaction) in tetrahydrofuran (THF), about 0-10 ℃ of reaction down, are obtained β-sulfoxide ketone (VII).Sulfoxide ketone (VII) with water-soluble acid isomerization, is made sulfoxide ketone reset (Pummerer) and becomes hemimercaptol (VIII).In reaction-inert solvent such as chloroform, handle hemimercaptol with neutralized verdigris list hydrate, obtain α-keto-aldehyde (IX).At reaction-inert solvent such as low-grade alkane alcohol, especially in the ethanol, under about 20 ℃-50 ℃, the keto-aldehyde of general formula (IX) and formaldehyde and ammonium hydroxide are reacted, (compound of I-f) is with the preparation imidazoles can easily to be translated into general formula.Can easily they be emanated out with its acid salt form.
Logical formula I compound, wherein X is that O and Y are above-mentioned heterocyclic ring (e), (g), (h), (i), (m) or (o), can be prepared according to program C.
Figure 87103225_IMG26
Figure 87103225_IMG27
In program C, reactant with general formula (X), can be from logical formula III compound, prepare with known method, this method comprises with as sodium borohydride aldehyde functional group being reduced into methylol, with triphenylphosphine-carbon tetrabromide alcohol being changed into corresponding bromo derivative and the bromo derivative that obtains is obtained (X) with the alkali metal cyanide reaction.(X) and ethyl formate are at the alpha proton reaction-inert solvent that resembles aromatic hydrocarbon or aliphatic hydrocarbon one class, for example benzene, toluene or hexane; Ether is for example in dioxan, tetrahydrofuran (THF), two (2-methoxy ethyl) ether; And the alkali of sufficient intensity is being arranged, and for example the existence of sodium hydride is carried out down, and reaction can form negatively charged ion on active methylene radical, with the compound of preparation general formula (XI).
It is by in reaction-inert solvent such as low-grade alkane alcohol that general formula (XI) is converted into general formula (XII), in envrionment temperature with at about 15-100 pound/inch 2(about 1-7 kilograms per centimeter 2) pressure under, carry out with Raney's nickel catalyst that catalyst hydrogenation finishes.Other noble metal catalyst also can use.Yet, use them may cause formyl radical to reduce, thereby avoid using with itrile group.In low-grade alkane alcohol and under about 50-100 ℃, handle enamine-aldehyde (XII) with hydrazine, just can easily (XII) be carried out cyclisation and become (I-e).Pyrazole derivatives (e) can be emanated by methods known in the art.
(I-g) is by enamine-aldehyde (XII) and thiocarbamide to 6-element heterocycle structure, exist down in hydrochloric acid or other strong acid, at reaction-inert solvent such as low-grade alkane alcohol or ether such as dioxan, tetrahydrofuran (THF), two (2-methoxy ethyl) ether and 1, reaction in the 2-glycol dimethyl ether and producing.Then, with the pyrimidone (reduction of I-g) and obtain (I-h) and/or (I-i).Will (I-g) as above-mentioned reaction-inert solvent of enumerating in, in from about 50 ℃ to the reflux temperature of selected solvent, with the Raney's nickel reduction, can obtain tetrahydro pyrimidine ketone (I-h).It further with Raney's nickel reduction, can be obtained hexahydropyrimidine ketone (I-i).In each above-mentioned reduction reaction, hydrogen pressure is from about 15-100 pound/inch 2Can cause gratifying productive rate.Certainly, if need, other catalyzer can be used in these reductive actions as noble metal catalyst.
In addition, (compound of I-i) can be by with suitable formula III 3-R for general formula 1-4-R 2O-phenyl aldehyde and cyanoacetic acid, in reaction-inert solvent such as pyridine, under piperidines, morpholine, piperazine or of the existence of other alkalescence greater than the alkali of pyridine, from envrionment temperature to about 120 ℃, prepare and preferably react under 50 ℃ of-100 ℃ of temperature.3-(3-R 1O-4-R 2The O phenyl) trimethylene cyanide can be disintegrated by known method, as: will also use appropriate solvent such as ethyl acetate extraction product in the reactant impouring water.Then with the trimethylene cyanide derivative in 0 ℃, in reaction-inert solvent such as aqueous acetone solution, handle with hydrogen peroxide and yellow soda ash, be converted into corresponding glutaramide derivatives.Reaction mixture slowly is heated to envrionment temperature, and be stirred to the reaction finish.Reaction mixture concentrated extraction and separate and obtain diamide.Then with 3-(3-R 1O-4-R 2O) glutaramide in reaction-inert solvent such as pyridine, under envrionment temperature, carries out cyclisation with the lead tetra-acetate reaction.Product separates by extracting.
With enamine aldehyde (XII) and 3-amino-pyrazol or 2-aminooimidazole, reaction produces general formula (I-m) and (compound of I-o) in the presence of mineral acid respectively.Though the above-mentioned reaction of enumerating-inert solvent can be used for preparation (I-g), and ethanol is favourable as solvent.Be reflected at from about 50 ℃ and to the reflux temperature of selected solvent, carry out.
Logical formula I compound wherein heterocyclic ring Y is above-mentioned (d), route system that can follow procedure D
Figure 87103225_IMG28
Aldehyde (III) and propanedioic acid two (C 1-5) alkyl ester such as diethyl malonate, at reaction-inert solvent such as benzene,toluene,xylene hexane, cyclic ethers, two (2-methoxy ethyl) ether, 1, in the 2-glycol dimethyl ether, and in the presence of piperidines, carry out Knoevenagel condensation in 50-150 ℃, can obtain undersaturated diester (X III).This diester in alcohol or other reaction-inert solvent, with the sodium cyanide reaction, is obtained cyano group ester (X IV) under envrionment temperature.This cyano group ester reduces with noble metal catalyst such as platinum oxide in acetate, obtains corresponding amino acid ester, then with it in aromatic hydrocarbon or above-mentioned, heat in the ether of mentioning in the Knoevenagel condensation, can cyclisation become corresponding α-ethyl ester lactan.The ethyl ester lactan is carried out saponification with ethanol-alkali metal hydroxide under refluxing, and institute's resultant is neutralized with sodium salt, can obtain α-carboxyl lactan, carry out decarboxylation with heating means in about 180 ℃ then, obtain pyrrolidone (I-d).
The route of the logical formula I compound of follow procedure E general introduction preparation, wherein X is O and Y is heterocycle (j), (k), (l), (n) and (p):
Figure 87103225_IMG29
In this program, the formula III compound is converted into methyl alcohol (X V) with well-known Grignard reaction.This alcohol is used Jones reagent then, carries out oxidation under the condition of the preparation formula VI compound that program B describes, and obtains corresponding ketone.This ketone under reflux temperature, at three-dimethylamino methylmethane, is promptly introduced in the reagent of dimethylamino ethylidene and handled, obtain the compound of formula (X VI).This multi-functional reactant can be used as heterogeneous ring compound of the present invention (I-j), (I-k), (I-l), (I-n) and (the key structure unit of I-p).
(X VI) and thiocarbamide react in alcoholic acid hydrochloric acid, obtain (I-j) or relevant compound, wherein heterocycle partly is the 4-(4-hydroxyl-1,2,3 of following formula, 4-tetrahydrochysene-2-pyrimidone):
Figure 87103225_IMG30
Or two types mixture of described compound.Thiocarbamide depends on the reaction times with the cyclisation product of (X VI).If be reflected at and reflux or when carrying out 1 hour under refluxing, obtain mainly be hydrate wherein heterocycle partly be (ja).If at about 2 hours, obtain the mixture of two kinds of products of about same amount heat-up time.If reach as 4-6 hour between the back is seasonable, obtain that (compound of I-j), main products are the (anhydro derivatives of compound of I-ja).
(compound of I-j) is as with Raney's nickel or noble metal catalyst reduction, obtains formula (I-k) or (compound of I-l).Specific product depends on reductive condition well known to those skilled in the art.
With the wherein Y of front is the hydrated compound of (ja), in alcoholic acid hydrochloric acid, heat, and until the element that removes fully in anhydrating, the production (compound of I-j).
General formula (X VI) compound and 2-aminooimidazole or 3-amino-pyrazol, respectively with above-mentioned preparation (I-o) and (I-m) react under the corresponding condition can easily obtain general formula (I-p) and (I-n).
Logical formula I compound, wherein XR 1Be-NH-R 1, by above-mentioned response procedures similar operation preparation.Difference is with suitable 3-nitro-4-OR 2Phenyl aldehyde, 3-nitro-4-OR 2Benzyl cyanide, or 3-nitro-4-OR 2Phenylformic acid is as starting raw material, the 3-OR among the alternative program A-E 1-4-OR 2The diether reactant.Described reactant is through above-mentioned response procedures, obtains in the formula I compound-XR 1Base is by nitro alternate compound.Described nitro as being amino with platinum oxide/hydrogen reduction, obtains corresponding aminoderivative by known method.Aminoderivative carries out standard reductive alkylation with suitable multi-ring alkyl ketone by the method that the present technique field is known, obtains wherein amino N H 2Be converted into-NHR 1The formula I compound.
Be applicable to above-mentioned each with and the preparation that can use the same method, also having Y wherein is following heterocycle generalformula one of partly,
Figure 87103225_IMG31
Z is a hydrogen, C 1-4Alkoxyl group, Cl and
N is 1 or 2.Described compound can be according at " India's The Chemicals " 18B, and general operation of describing in 428 pages (1979) prepares.Operation comprises the 3-R of the above-mentioned logical formula III of gram molecular weights such as using 1O-4-R 2The 6-person of O phenyl aldehyde and suitable condensed ring system encircles the ortho position-diamines (as: 1, the 2-diaminobenzene) of composition, reacts in oil of mirbane in 100 ℃.Oil of mirbane is as solvent or oxygenant.Reaction was finished at 2-3 hour usually.Product separates with currently known methods, comprises using the flash chromatography on silica gel column chromatography.
Acid salt with logical formula I compound of a basic group, can by to preferably can be partly dissolved at least at solvent logical formula I compound in logical formula I compound in, the suitable acid that adds stoichiometric quantity prepares.If the acid salt that obtains is dissolved in solvent systems, it can be by with solvent evaporation or add a solvent that can not dissolve this salt and salt is precipitated out separate from the solvent of reaction.
The compounds of this invention with logical formula I has the C-AMP(ring gland glycosides of calcium independent) the phosphodiesterase inhibit feature, and can be used as counter inhibitor.Be used in " Acta Biochimica et Biophysica Sinica " 797,354-362 page or leaf (1984), the Davis method of last report is measured their activity as the C-AMP phosphodiesterase inhibitor of calcium independent.In this method, calcium independent-to belong to phosphodiesterase (being respectively IPDE and DPDE) with calcium be with female Si Puleige-Dao Li (Sprague-Dawley) mouse pallium preparation, at first cerebral tissue is placed on and contains 1 mmole Mgcl simultaneously 2,, 3 mmoles-2 mercapto ethanol and 0.1 mmole EGTA(1,2-ethylidene glycol-two-(beta-aminoethyl ether)-N, N '-four acetic acid) pH be homogenizing in the damping fluid of 7.5 20 mmole Tutofusin triss-HCl(Tris-CHl).Tissue homogenate is 105, and under the 000Xg centrifugal 60 minutes, the supernatant liquor that will contain divided DPDE and EPDE and opens by the crosslinked bacterium glycan of Sephadex G-200 gel column.Two phosphodiesterases are further purified by Calmodulin-Sepharose post affinity chromatography chromatography respectively.
The activity of di(2-ethylhexyl)phosphate sparrow hawk enzyme is to contain Tutofusin tris pH7.5 damping fluid (5 micromole), MgCl with 0.1 milliliter 2(0.5 mmole) and (3H) CAMP(NEN, reaction mixture NET-275) is measured.The ultimate density of CAMP is (3H) CAMP of 1.0 micromoles (contain 400,000dpm(decay/minute)).With IPDE or the DPDE or the relevant enzyme that boiled of 10 microlitre vehicles or inhibitor solution and 10 microlitre new systems, add the Tris-HCl/MgCl that 80 microlitres contain enzyme substrate 2In the damping fluid.Reaction mixture was 37 ℃ of hatchings 8 minutes, and be positioned in the hot water bath 2 minutes to stop the hydrolysis of CAMP, with 5 '-0.5 mmole 5 of AMP(0.5 milliliter '-AMP is at 0.1 mole of Hepes(N-2-hydroxyethyl piperazine-N '-2-ethylsulfonic acid)-0.1 mole of NaCl pH8.5 damping fluid) in carrier add, and the reaction mixture that will hatch in the pipe pours in the post of polyacrylamide-borate affinity glue (Bio-Rad affinity gel 601 borate glue), with wash-out in 7.5 milliliters of 0.1M Hepes-NaCl damping fluid gels.With 7.5 milliliters of 0.1M Hepes-NaCl damping fluids with (3H) CAMP wash-out from gel.With 7 milliliter 50 the milli MpH4.8 sodium-acetate buffer wash-out (3H) 5 '-the AMP product.Get the aliquots containig of the latter's 1 milliliter of elutriant, put into liquid scintillation counter and count, measure their radioactivity 5 '-content of AMP.
Various through disease and psychological disorders when being used for the treatment of dysthymia disorders with other, when especially de-addiction, anxiety, ideological stumbling-block and vain hope, they can its original form use, or use with the pharmaceutical compositions that comprises logical formula I compound and pharmaceutically acceptable carrier or thinner.For oral medication, the best approach of using described compound and suitable pharmaceutical carrier comprises inert diluent or weighting agent, treats as the dosage form of tablet, powder, capsule etc. to form.These pharmaceutical compositions also can contain if necessary just like perfume agent, binding agent, the other composition of vehicle etc.For example: contain different vehicle, as the tablet of Trisodium Citrate, with different disintegrating agent such as starch, alginic acid and some silicate composites, and with binding agent such as Polyvinylpyrolidone (PVP), sucrose, gelatin and gum arabic etc. use together.In addition, lubricant such as Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum powder are commonly used to make tablet.Similarly solids composition also can be used as weighting material in the gelatine capsule of soft and hard filling.Therefore, best material comprises lactose or toffee and high-molecular weight polyoxyethylene glycol.
For oral dispenser, promoting agent dosage every day of logical formula I is from about 0.1 milligram to about 10 milligrams, and for the parenteral dispenser, preferably intravenous injection or intramuscular injection, every day, dosage was from about 0.01 milligram to about 5 milligrams.Certainly, the doctor who prescribes is according to such as the severity of patient symptom and the patient factors such as reaction to concrete medicine, with a certain patient's of final decision open suitable dosage.
The antidepressant activity of The compounds of this invention is with people such as Porsolt, and at Inpharm document 227,327-336(1977) the desperate example of the behavior of upward narrating is determined.
In this experiment, force mouse in the narrow shape right cylinder that water is housed that can not run away, to swim, add and send out mouse generation depressive state.This experiment makes to comprise the test compound to each mouse injection port dosing, and (injects back 30 minutes) then mouse is placed in the glass beaker of standard 1 liter that 800 milliliters of 25 ℃ of water are housed.
Begin to observe mouse in back 2 minutes putting into water then, in 5 minutes, determined the movability (0=is removable, and 1=does not move) of a mouse in per 30 seconds.
With body weight is the male CD(Charles River of 20-25 gram) mouse (10 every group), test.Test compound added contains 0.9% physiological saline (90%), dimethyl sulfoxide (DMSO) (5%) and emulsion 4(5%) solution (vehicle).All medicine volume injected are 10 milliliters/kilogram.The general swimming number of times of handling with vehicle of mouse is 9, but thymoleptic can reduce mobile numerical value, and the result has reduced the number of times of swimming.
Second experiment is that people such as Koe is published in " pharmacological evaluation treatment magazine " 226, and the method for 686-700 page or leaf (nineteen eighty-three) is resisted the performance of serpentine cooling in mouse comprising the determination test medicine.In this experiment, it is in 20 ℃ the room that mouse is placed on room temperature.Every mouse is put into the plastic containers that have at the bottom of the cardboard respectively, kept 18 hours to mouse injection serpentine (1.0 milligrams/kilogram subcutaneous) and in 18-19 ℃.So after they accept physiological saline or drug treating, can determine their rectal temperature immediately.Usually measured rectal temperature in 1,2 and 4 hour once more in the injection back for the second time at this kind.The mean value that the result increases with serpentine-inhibition temperature.In general, the serpentine of injection Vehicle-pre-treatment mouse was being handled with vehicle back 4 hours, showed the about 20-22 of average rectal temperature ℃.Handle with the known thymoleptic piptonychia third flavor piperazine (10 milligrams/kilogram oral), obtain the about 30-33 of average rectal temperature ℃ (increasing 40-50% approximately).Use logical formula I compound, cause the increase of the rectal temperature of lab mice.
The emetic action of logical formula I compound is littler than the woods than the Raleigh, thereby is better than the Raleigh and compares woods.Their emetic performance is measured by giving the dog dispenser, and trial drug is dissolved in the ethanol with 10 mg/ml, and drug dose with distilled water diluting to the final volume of selecting, alcoholic acid content is no more than 10% in the last solution.Drug solution is by oral gavage administration, and used volume is calculated as 2 milliliters/kilogram with body weight, observes the vomiting phenomenon of dog then.If the vomiting phenomenon takes place, record latent period (during to time that the vomiting phenomenon takes place) from injection.If do not vomit, then another is tested the come into operation medicine of a higher dosage of dog at 30 minutes.The initial dose that uses is 100 microgram/kilograms, is the subliminal dose of Raleigh than woods.
The following example and preparation, only the invention will be further described.The abbreviation of following peak shape is to be used to report the H-nmr(nucleus magnetic resonance) value: bs is wide unimodal; S, unimodal; D, doublet; T, triplet; Q, quartet; M, multiplet.In embodiment and preparation and under wrapsly make any given reaction obtain optimum yields.
Example 1
α-N-methylamino--3-(dicyclo (2.2.1) heptan-2-base oxygen) 4-p-methoxybenzeneacetonitrile
Dicyclo (2.2.1) heptan-2-base ether (0.14 mole of 3.5 gram) of getting preparation Z is dissolved in 50 milliliters of ethanol, to wherein adding sodium cyanide (0.736 gram, 0.15 mole) and methylamine hydrochloride (1.0 restrain 0.15 mole), then in stirring at room 18 hours.Reaction mixture dilutes with saturated sodium bicarbonate, and extracts with ether (3 * 30 milliliters).The organic layer that merges with saturated nacl aqueous solution (3 * 30 liters) washing, through anhydrous sodium sulfate drying, is filtered and gets 4.15 gram (～100%) transparent oily cyano group amine in vacuum-drying.The cyano group amine that obtains is in 7: 3 of bicyclic alkyl ether: outer mixture.
H Nmr(nucleus magnetic resonance) (300HMz, CDCl 3): δ 7.2-6.8(m, 3H), 4.72(bs, 1H), 4.6-4.7(m .7H) (interior), 4.2-4.3(m .3H) (outward), 3.9(bs, 3H), 3.5(m, 1H), 2.6(bs, 3H), 2.7-1.0(m, 10H).
Carry out following conversion with similar approach:
With-three ring (3.2.1.0 in the 3-( 2,6) last of the ten Heavenly stems-8-base oxygen)-the 4-methoxybenzaldehyde is converted into corresponding amino-nitrile, yield 89.4%.
1H NMR（300MHz，CDCl 3）：delta 7.1-6.81（m，3H），4.7（bs，1H），4.6（m，1H），3.9（s，3H），2.6（s，3H），2.8-1.0（m，14H）;
With outer-three ring (3.2.1.0 of 3-( 2,6) last of the ten Heavenly stems-4-base oxygen)-the 4-methoxybenzaldehyde is converted into corresponding amino-nitrile, yield 97.2%.
1H NMR（300MHz，CDCl 3）：delta7.1（m，2H），6.9（m，1H），4.9（m，1H），4.75（s，1H），3.9（s，3H），2.65（s，3H），2.6（m，2H），2.3-1.2（m，12H）;
With 3-outer-benzo dicyclo (2.2.1) heptan-2-base oxygen)-the 4-methoxybenzaldehyde changes into corresponding amino-nitrile, yield is similar to 100%.
1H-NMR（300MHz，CDCl 3）：delta 7.4-6.9（m，7H），4.6（bs，1H），4.4（m，1H），3.9（s，3H），3.6（bs，1H），3.4（bs，1H），3.35（bs，1H），2.5（bs，3H），2.25（m，1H），1.95（m，3H）;
In the 3-(-benzo dicyclo (2.2.1) heptan-2-base oxygen)-the 4-methoxybenzaldehyde changes into corresponding amino-nitrile, yield 100%.
1H NMR（300MHz，CDCl 3）：delta7.2-6.95（m，6H），6.8（m，1H），5.1（m，1H），4.7（bs，1H），3.7（m，1H），3.61（bs，3H），3.2（m，1H），2.6（s，3H），2.5（m，1H），1.9（m，1H），1.8（m，1H），1.25（m，1H）;
-three ring (3.2.1.0 in the 3-( 2,6) last of the ten Heavenly stems-8-base oxygen)-the 4-methoxybenzaldehyde changes into corresponding amino-nitrile, yield 95.4%.
1H NMR（300MHz，CDCl 3）：delta7.0-6.7（m，3H），4.7（m，1H），4.65（bs，1H），3.87，3.85（s，3H），[2-methoxyls]，2.5（bs，3H），2.2-2.5（m，14H）。
Example 2
2-methylamino--2-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) ethylamine
In one the 1 dry round-bottomed flask of crossing of liter flame, add hydrogenation Di-Isobutyl aluminium (solution of 46.6 milliliters of 0.07 mole of DiBal-H in 1.5 moles of toluene) and 150 milliliters of dry toluenes.This hydride solution is cooled to-78 ℃, and the introversive cyano group amine (4.00 grams, 0.014 mole) that wherein drips example 1 was formed on 250 milliliters of solution in the dry toluene in 1 hour.Reaction mixture was stirred 2 hours in-78 ℃, and be warming up to 0 ℃ lentamente, the saturated solution (10 milliliter) of this moment by dripping Seignette salt inhibited reaction slowly.When gas is overflowed no longer obviously, carefully add 40 milliliters of tartrate solution again, and reaction is warming up to room temperature.Reaction slurry is diluted with 150 milliliters of ether, and with ether (2 * 50 milliliters) aqueous layer extracted, with saturated tartrate solution (2 * 50 milliliters), water (2 * 50 milliliters) and saturated nacl aqueous solution (2 * 50 milliliters) wash with the ether layer that merges.The organic layer anhydrous magnesium sulfate drying filters, and gets 3.19 gram faint yellow oily diamines (78.5%) in vacuum concentration.The diamines that obtains is dicyclo (2.2.1) heptan-2-base oxygen ether mixture of interior and outer (7: 3).
Prepare following 2-methylamino-2-(3-(R with similar approach from suitable reactant 1O)-and the 4-p-methoxy-phenyl) ethylamine:
R 1In the O=-and benzo dicyclo (2.2.1) heptan-2-base oxygen, yield 39%.
1H NMR（300MHz，CDCl 3）：delta7.2-6.7（m，7H），5.2（m，1H），3.7（m，1H），3.6（s，3H），3.2（m，2H），2.85（m，2H），2.5（m，1H），2.4（s，3H），1.9（m，1H），1.8（m，1H），1.2（m，1H）;
R 1O=is outer-benzo dicyclo (2.2.1) heptan-2-base oxygen, and yield 94.5%.
R 1-three ring (3.2.1.0 in the O= 2,6) last of the ten Heavenly stems-4-base oxygen, yield 96%.
1H NMR（300MHz，CDCl 3）：delta 6.8-6.7（m，3H），4.75（m，1H），3.78（s，1H），3.38（m，1H），2.8（m，2H），2.3（s，3H），2.4-.9（m，14H）。
1H NMR（300MHz，CDCl 3）：delta 6.7-7.0（m，3H），4.6（m，.7H），4.2（m，.3H），3.8（bs，3H），3.64（bs，1H），3.33（m，1H），2.7-2.85（m，2H），2.3（bs，3H），2.5-1.0（m，10H）。
Prepare following diamines with similar approach from suitable reactant: 2-methylamino--2-(-three ring (3.2.1.0 in the 3-( 2,6) last of the ten Heavenly stems-8-base oxygen)-the 4-p-methoxy-phenyl) ethylamine, yield approximate 100%.
1H NMR（300MHz，CDCl 3）：delta7.0-6.8（m，3H），5.7（m，1H），3.9（s，3H），3.5（m，1H），3.0-1.0（m，19H）.
2-methylamino--2-(-three ring (3.2.1.0 in the 3-( 2,6) last of the ten Heavenly stems-4-base oxygen)-the 4-p-methoxy-phenyl) ethamine, yield 76.62%.
Example 3
1-methyl-5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-the 2-imidazolone
The diamines (3.19 grams, 0.11 mole) of getting example 2 is dissolved in the anhydrous tetrahydro furan, and with 1,1-carbonyl dimidazoles (2.67 grams, 0.0165 mole) is handled.With reaction mixture in stirring at room 24 hours.Ethyl acetate extraction (2 * 30 milliliters) will also be used in reaction mixture impouring 50 ml waters, with the organic layer 1N sodium hydroxide solution (2 * 30 milliliters) that merges, 1N hydrochloric acid (2 * 30 milliliters), water (2 * 30 milliliters), and saturated salt solution (3 * 30 milliliters) washing, organic layer is through anhydrous sodium sulfate drying, filter and vacuum concentration gets transparent oil, with ether develop the imidazolone of 622 milligrams of (yield 17.8%) white solids.Fusing point: 142-144 ℃.Product is the mixture of 2 pairs of diastereomers.
1H NMR（250MHz，CDCl 3）：delta6.7-6.85（m，3H），5.7（bs，1H），4.6（m，.7H），4.4（m，1H），4.2（m，.3H），3.82（s，2.1H），3.80（s，.9H），3.68（dd，J＝11.5Hz，J＝8Hz），3.21（dd，J＝11.5，J＝8.1Hz），2.6（s，3H），2.6-1.0（m，10Hz）.
13C NMR（63HH 2，CDCl 3）：delta 163.2，149.8，148.7，131.7，119.3，113.2，112.3，112.2，112.0，78.9，78.8，62.84，62.81，56.15，56.0，47.5，41.1，40.5，39.9，37.2，37.1，36.7，35.4，35.3，29.4，28.74，28.70，28.3，24.2，20.7（30 lines）.
MS：M+＝316.0，222.1，95
Same, the diamines cyclisation with suitable can prepare following imidazolone: 1-methyl-5-(-three ring (3.2.1.0 in the 3-( 2,6) last of the ten Heavenly stems)-8-base oxygen)-the 4-p-methoxy-phenyl)-the 2-imidazolone, yield 20.7%.
Fusing point: 149-152 ℃
1H NMR（300MHz，CDCl 3）：delta6.9-6.8（m，3H），5.15（bs，1H），4.65（m，1H），4.5（m，1H），3.9（s，3H），3.75（m，1H），3.25（m，1H），2.7（s，3H），2.8-1.0（m，14H）.
HRMS 356.2120 Calcd.for C 21H 28N 2O 3356.2099.
C 21H 28N 2O 3Molecular weight calculated value=356.2099
HRMS(high resolution capacity mass spectrograph) molecule measuring definite value=356.2120
Ultimate analysis:
The calculated value measured value
C 70.76 70.72
H 7.92 7.86
N 7.86 7.79
1-methyl-5-(outer-three ring (3.2.1.0 of 3-( 2,6) last of the ten Heavenly stems-4-base oxygen)-the 4-p-methoxy-phenyl)-the 2-imidazolone, yield 11.42%.
1H NMR（300MHz，CDCl 3）：delta6.8（m，3H），6.1（bs，1H），4.8（m，1H），4.4（m，1H），3.8（bs，3H），3.7（m，1H），3.2（m，1H），2.6（s，3H），3.6-1.2（m，14H）.
13C NMR（75.43MHz，CDCl 3）：delta163.3，150.1，148.2，131.9，119.6，113.6，112.1，83.4，56.0，47.5，43.2，42.3，40.6，32.7，29.6，28.7，23.2（17lines）。
Ultimate analysis:
C 21H 28N 2O 3Calculated value: C, 70.75; H, 7.91; N, 7.86.
Measured value: C, 68.76; H, 7.61; N, 8.35.
1-methyl-5-(in the 3--benzo dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl)-the 2-imidazolone, yield 13.74%.
1H NMR（300MHz，CDCl 3）：delta7.2-7.05（m，4H），6.8（m，3H），5.1（m，1H），4.85（bs，1H），4.45（m，1H），3.7（m，1H），3.68（m，1H），3.4（m，1H），3.25（m，1H），2.65（s，1H），2.45（m，1H），1.9（m，1H），1.8（m，1H），1.25（m，1H）;
1-methyl-5-(3-is outer-benzo dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl)-the 2-imidazolone, yield about 17%.
1H NMR（300MHz，CDCl 3）：delta7.2-7.1（m，4H），7.0-6.9（m，3H），4.5（m，1H），4.4（m，1H），3.9（s，1H），3.75（m，1H），3.6（bd，1H），3.4（bs，1H），3.25（m，1H），2.67+2.65（s，3H），2.25（m，1H），1.95（m，3H）.
Ultimate analysis:
C 22H 24N 2O 3Calculated value: C, 72.50; H, 6.63; N, 7.68.
Measured value: C, 71.73; H, 6.78; N, 7.28.
1-methyl-5-(-three ring (3.2.1.0 in the 3-( 2,6) last of the ten Heavenly stems-4-base oxygen)-the 4-p-methoxy-phenyl)-the 2-imidazolone, yield 7.2%.
1H NMR（300MHz，CDCl 3）：delta6.8-6.7（m，3H），5.75（bs，1H），4.75（bs，1H），4.42（m，1H），3.83（s，3H），3.72（m，1H），3.28（m，1H），2.65（s，3H），2.3-.9（m，14H）。
13C NMR（75.4MHz，CDCl 3）：delta163.2，150.8，147.8，131.8，120.0，114.5，112.4，82.5，62.8，56.2，47.6，46.2，40.4，37.7，31.8，28.8，28.5（17lines）。
Ultimate analysis:
C 21H 28N 2O 3Calculated value: C, 70.75; H, 7.91; N, 7.86.
Measured value: C, 69.74; H, 7.93; N, 7.48.
Example 4
1-normal-butyl-3-methyl-4-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) 2-imidazolone
The imidazolone (0.5 gram, 1.58 mmoles) of getting example 3 is dissolved in 20 milliliters of tetrahydrofuran (THF)s (THF) and the 5 milliliters of dimethyl glyoximes (DMG), with sodium hydride (41 millis, 1.73 mmole) handle, be cooled to 0 ℃, just using-butyl iodide (0.581 gram, 3.15 mmoles) to handle.Reaction mixture is warming up to room temperature lentamente, stirred 24 hours.Dilute with water extracts with ether then.Organic layer water, salt solution, washing are through MgSO 4Drying is filtered and vacuum concentration, and product is developed with ether, gets 211 milligrams of (35.8%) products.Products obtained therefrom is the isomer mixture of inside/outside (7: 3).
Ultimate analysis:
C 22H 32N 2O 3Calculated value: C, 70.93; H, 8.66; N, 7.52.
Measured value: C, 69.95; H, 8.66; N, 7.43.
Example 5
1-ethanoyl-3-methyl-4-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-the 2-imidazolone
Repeat the step of example 4, but with suitable book Acetyl Chloride 98Min. alternative just-butyl iodide, obtain this title compound, yield 29.3%.
Ultimate analysis (hemihydrate):
C 20H 16N 2O 41/2H 2O calculated value: C, 65.44; H, 7.41; N, 7.63.
Measured value: C, 65.36; H, 7.29; N, 7.00.
Example 6
1,3-dimethyl-4-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-the 2-imidazolone
Repeat the step of example 4, but just substituting-methyl iodide, obtain this title compound, yield 56.3% with the methyl iodide of stoichiometric quantity.
Ultimate analysis:
C 19H 26N 2O 3Calculated value: C, 68.86; H, 7.90; N, 8.45.
Measured value: C, 68.57; H, 7.87; N, 8.14.
Example 7
1-methyl-5 (3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-1,2,3-thio biphosphole 2,2-dioxide
The diamines (3.3 grams, 11.37 mmoles) of getting example 2 is dissolved in 180 milliliters of anhydrous pyridines, with sulphonamide (1.36 grams, 14.22 mmoles).The reaction mixture intensification is refluxed, and refluxed 15 hours.Reaction mixture is cooled to room temperature, and with the dilution of 500 milliliters of ether, with 5 * 100 ml waters, 5 * 100 milliliters of 1N HCl and 2 * 200 ml waters wash.Organic layer filters and vacuum concentration through anhydrous sodium sulfate drying.Rough resistates is made eluent through the SiO chromatography with 50% vinyl acetic monomer/hexane.Collect suitable part, concentrate 1.35 gram (yield 33.7%) orange solid cyclic sulfonamides.
Fusing point: 55.57 ℃
1H NMR（300MHz，CDCl 3）：delta6.85-6.7（m，3H），4.7-4.5（m，1.5H），4.3-4.1（m，1.5H），3.8（bs，3H），3.65（m，1H），3.3（m，1H），2.51（bs，3H），2.6-1.0（m，10H）。
C 17H 24N 2O 4S, molecular weight calculated value: 352.1466
HRMS(M+) molecule measuring definite value: 352.1457
Example 8
1-methyl-5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-the 2-imidazolidinethione
The diamines (2.3 grams, 7.93 mmoles) of getting example 2 is dissolved in 65 milliliters of tetrahydrofuran (THF)s, uses N, and N-thiocarbonyl imidazoles (1.76 grams, 9.91 mmoles) is handled.With reaction mixture in stirring at room 41 hours.Reaction mixture is diluted with 250 milliliters of ether.Collected organic layer is with 1 * 80 ml water, 2 * 100 milliliters of 0.5N NaOH solution, and 2 * 100 milliliters of 0.5N HCl solution, the washing of 1 * 100 ml water, organic layer filters and vacuum concentration through anhydrous magnesium sulfate drying.Resistates is made elutriant through the purifying of fast silica gel chromatogram layer folding with 50% vinyl acetic monomer/hexane.Collect suitable part, concentrate in the thiocarbamoyl imidazole quinoline ketone of 1.7 gram (65.5%) faint yellow solids: the mixture of outer (7: 3).
Alkane point: 149-150.5 ℃
1H NMR（250MHz，CDCl 3）：delta6.9-6.7（m，3H），6.15（bs，1H），4.7（m，1H），4.6（m，.7H），4.2（m，.3H），3.9（m，3H），3.86（s，2.1H），3.83（s，.9H），3.42（m，1H），2.93（bs，3H），2.6-1.1（m，10H）。
C 18H 24N 2SO 2Molecular weight calculated value: 332.1583
HRMS(M+) molecule measuring definite value: 332.1559
Example 9
α-N-methylamino--3-(is outer-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxybenzeneacetonitrile
Get 3-(outer-(dicyclo (2.2.1) heptan-2-base oxygen)-4-methoxybenzaldehyde (4.22 grams, 17.0 mmoles) is dissolved in 60 milliliters of ethanol, with methylamine hydrochloride (1.40 grams, 21.27 mmoles) and cyanogen water sodium (1.04 grams, 21.27 mmoles) processing.In reaction mixture, add 15 ml waters, make uniform mixture, with reaction mixture in stirring at room 72 hours.Reaction mixture is diluted with 250 milliliters of ethers, with 3 * 100 ml waters and 1 * 100 milliliter of saturated nacl aqueous solution washing.Organic layer is through dried over mgso, and filtering also, vacuum concentration gets 4.45 gram (91%) transparent faint yellow oily amino-nitriles.
1H NMR（300MHz，CDCl 3）：delta7.1-6.8（m，3H），4.7（bs，1H），4.25（m，1H），3.88（s，3H），2.56（s，3H），2.5-1.0（m，10H）。
Example 10
2-methylamino--2-(3-(is outer-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) and ethylamine
Outer-dicyclo (2.2.1) heptan-2-base oxygen-amino-nitrile (4.45 grams, 15.56 mmoles) of getting example 9 is dissolved in 100 milliliters of dry toluenes, this solution is added to-78 ℃ Dibal-H(70.01 mmole) in the solution of 300 milliliters of toluene.Reaction mixture was stirred 4 hours in-78 ℃, remove cooling bath, the solution that dropwise adds 100 milliliters of saturated sodium tartrate/potassium is inhibited reaction lentamente.Sluggish rises to room temperature and dilutes with 500 milliliters of vinyl acetic monomers.Water layer and organic layer are separated, and water layer is saturated and with 1 * 100 milliliter of dichloromethane extraction with sodium-chlor.The organic layer of collecting is washed with 1 * 100 milliliter of saturated sodium tartrate/potassium solution and 2 * 100 milliliters of saturated nacl aqueous solutions.Organic layer is through the salt of wormwood drying, filters and vacuum concentration makes the (90% outer-dicyclo (2.2.1) heptan-2-base oxygen-diamines of 4.0 gram clear, viscous oil.
1H NMR（300MHz，CDCl 3）：delta6.83（m，3H），4.22（bd，1H），3.83（s，3H），3.38（m，1H），2.84（m，2H），2.3（s，3H），2.5-1.0（m，10H）。
Example 11
1-methyl-5-(3-is outer-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl)-the 2-imidazolone
Outer-dicyclo (2.2.1) heptan-2-base oxygen-diamines (4.0 grams, 13.79 mmoles) of getting example 10 is dissolved in 170 milliliters of tetrahydrofuran (THF)s and use N, N-carbonyl dimidazoles (2.8 grams, 17.24 mmoles) processing.With reaction mixture in stirring at room 40 hours.Reaction mixture is diluted with 300 milliliters of ether, with 1 * 100 ml water; 1 * 100 milliliter of 0.5N sodium hydroxide solution, with 1 * 100 milliliter of 0.5N HCl solution and the washing of 1 * 100 ml water, organic layer filters and vacuum concentration through dried over sodium sulfate.Resistates is made elutriant through the flash chromatography on silica gel purifying with 50% vinyl acetic monomer/hexane.Collect the imidazolone that suitable part and vacuum concentration make 1.60 gram (36.7%) white powders.Fusing point 148-151 ℃.
1H NMR（300MHz，CDCl 3）：delta6.8（m，3H），5.3（3，1H），4.4（m，1H），4.2（bd，1H），3.80（s，3H），3.68（dd，J＝11.5Hz，J＝8Hz），3.21（dd，J＝11.5Hz，J＝8.1Hz），2.6（s，3H），2.5-1.0（m，10Hz）。
13C NMR（63MHz，CDCl 3）：delta163.12，150.03，147.63，131.67，119.43，119.35，112.92，112.82，112.02，81.04，62.74，56.0，47.46，41.0，39.79，35.33，35.23，28.63，28.25，24.15（20lines）。
C 18H 24N 2O 3Molecular weight calculated value: 316.1787
HRMS(M+) molecule measuring definite value: 316.1816
Example 12
In α-N-methylamino--3-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxybenzeneacetonitrile
Press the step of example 1,, obtain 3.8 gram products (95%) with aldehyde (3.46 grams, 14.06 mmoles) (preparation AA) preparation amino-nitrile.
1H NMR（300MHz，CDCl 3）：delta7.0-6.75（m，3H），4.62（bs，1H），4.7-4.5（m，1H），3.82（s，3H），2.65（m，1H），2.6（bs，3H），2.3（m，1H），2.05（m，2H），2.2-1.1（m，6H）。
Example 13
2-methylamino--2-3-(interior-dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) ethylamine
Press the step of example 2, the amino-nitrile (3.8 grams, 13.28 mmoles) that makes with example 12 prepares diamines, obtains 3.9 gram (～100%) products.
1H NMR（300MHz，CDCl 3）：delta6.9-6.7（m，3H），4.7（m，1H），3.91（s，3H），3.96（m，1H），2.96（m，2H），2.6（m，1H），2.3（bs，3H），2.3-1.0（m，9H）。
Example 14
1-methyl-5-(in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl)-the 2-imidazolone
Diamines (3.9 grams, 13.44 mmoles) preparation imidazolone by example 4 methods make with example 13 obtains 1.6 gram (38%) white solid product.
Fusing point: 148-149.5 ℃
1H NMR（300MHz，CDCl 3）：delta6.85-6.65（m，3H），4.6（m，1H），4.45（m，1H），3.83（s，3H），3.68（m，1H），3.2（m，1H），2.6（s，3H），2.55（m，1H），2.3-1.1（m，9H）。
13C NMR（63MHz，CDCl 3）：delta163.1，149.9，148.8，131.7，119.3，112.4，112.26，112.11，79.01，62.82，62.84，56.21，47.5，40.61，37.26，37.23，37.13，36.77，29.42，28.76，28.73，27.32，29.74（23lines）。
Some doublet is owing to a little diastereomer causes.
Example 15
Outside α-N-methylamino--3-(-dicyclo (2.2.2) suffering-2-base oxygen)-the 4-p-methoxybenzeneacetonitrile
Dicyclo (2.2.2) Octyl Ether (3.30 grams, 12.7 mmoles) of getting preparation BB is dissolved in 50 milliliters of ethanol, and adds methylamine hydrochloride (1.28 grams, 19 mmoles) and sodium cyanide (930 milligrams, 19 mmoles) in this solution.In this suspension, dropwise add entry, till the reaction mixture clarification.Reaction mixture was stirred 15 hours, and then handle with methylamine hydrochloride (320 milligrams, 4.75 mmoles) and sodium cyanide (232 milligrams, 4.75 mmoles).With reaction mixture in stirring at room 24 hours.Reaction mixture is diluted with 250 ml waters and 250 milliliters of ether.The water layer that produces extracts repeatedly with 100 milliliters of ethers, with the organic layer that merges, with 1 * 200 milliliter of 1N NaOH solution, 2 * 200 ml waters and 1 * 100 milliliter of salt solution washing, organic layer filters and makes in vacuum concentration the amino-nitrile of 3.80 gram (～100%) viscous oils through dried over mgso.Obtaining product need not be further purified and just can be used for example 16.
Example 16
2-methylamino--2-(outside the 3-(-dicyclo (2.2.1) suffering ,-2-base oxygen)-the 4-p-methoxy-phenyl) ethylamine
In-78 ℃ and 1 hour, to the Dibal-H(64.5 mmole) in the solution in 140 milliliters of toluene, dropwise add the solution of cyano group amine (3.80 grams, 12.7 mmoles) in 50 milliliters of toluene that example 15 makes.After dropwising, with reaction mixture-78 ℃ of following restir 1.5 hours.Reaction mixture is suppressed at-78 ℃ of saturated solutions with Seignette salt (5 milliliters), slowly rise to room temperature and then drip 100 milliliters of saturated potassium sodium tartrate solution processing reaction, and stirred 15 hours.Suspension is diluted with 100 milliliters of vinyl acetic monomers, and water layer is saturated with sodium-chlor, and with 2 * 100 milliliters of ethyl acetate extractions, the organic layer of inhaling collection is washed with salt solution, through dried over mgso, filter, make the aryl diamine of 3.14 gram (81%) viscous oils in vacuum concentration.Product can be used for the operation of example 17.
Example 17
1-methyl-5-(outside the 3-(-dicyclo (2.2.1) suffering-2-base oxygen)-p-methoxy-phenyl)-the 2-imidazolone
The aryl diamine (3.14 gram, 10.3 mmoles) of getting example 16 was dissolved in 100 milliliters of anhydrous tetrahydro furans, use N, and the N-carbonyl dimidazoles is handled (2.09 restrain 12.9 mmoles), in stirring at room 90 hours.Reaction mixture dilutes with 200 milliliters of ethers, with 1 * 50 milliliter of 2.5%HCl solution, and 1 * 50 milliliter of HO and 1 * 50 milliliter of 1N NaOH solution, 1 * 50 milliliter of HO and 1 * 50 milliliter of common salt aqueous solution washing.Organic layer filters, in vacuum concentration through dried over mgso.Resistates SiO(32-64) chromatography is made elutriant with 20% hexane/80% vinyl acetic monomer, absorbs suitable part, makes the imidazolone of 1.10 gram (32%) white solids in vacuum concentration.Fusing point: 142-146 ℃.
1H NMR（300MHz，CDCl 3）：delta6.85-6.65（m，3H），5.4（bs，1H），4.45-4.3（m，2H），3.8（s，3H），3.65（m，1H），3.2（m，1H），2.55（bs，3H），2.1-1.2（m，12H）。
13C NMR（75.6MHz，CDCl 3）：delta163.2，163.14，150.46，150.43，147.9，131.7，119.68，119.63，113.54，113.4，112.3，76.24，76.18，62.86，62.80，62.76，56.22，47.61，34.86，28.80，28.41，25.37，24.62，23.42，19.21（25lines）。
Some doublet is owing to a little diastereomer causes.
C 19H 26N 2O 3Calculated value=330.1924
HRMS(M+) measured value=330.1943
Example 18
Outside α-N-methylamino--3-(-dicyclo (3.2.1) suffering-2-base oxygen)-the 4-p-methoxybenzeneacetonitrile
Get the aryl ethers aldehyde (1.68 grams, 6.46 mmoles) that from preparation CC, makes and be dissolved in 50 milliliters of ethanol, handle with sodium cyanide (0.379 gram, 7.75 mmoles) and methylamine hydrochloride (0.519 gram, 7.75 mmoles).With reaction mixture in stirring at room 24 hours, with saturated NaHCO 3Solution dilutes reaction mixture furnishing alkalescence with 50 ml waters.Water layer extracts with 3 * 30 milliliters of ethers, and the organic layer of merging has 2 * 30 ml waters and 2 * 30 milliliters of salt solution washings, through Na 2SO 4Drying is filtered, and makes the transparent orange oil of 1.65 grams (89.5%) in vacuum concentration and is amino-nitrile.
1H NMR（300MHz，CDCl 3）：delta7.05-6.75（m，3H），4.65（bs，1H），4.45（m，1H），3.83（s，3H），2.55（bs，3H），2.3（m，1H），2.05（m，1H），1.8-1.3（m，10H）。
Example 19
2-methylamino--2-(outside the 3-(-dicyclo (3.2.1) suffering-2-base oxygen)-the 4-p-methoxy-phenyl) ethylamine
Will be at (20.25 milliliters 1.5 moles the toluene solution of the diisobutylaluminium hydride solution in 200 milliliters of dry toluenes, 0.028 mole), be cooled to-78 ℃, and dropwise add the solution of amino-nitrile (1.65 grams, 5.76 mmoles) in 25 milliliters of toluene that obtains from example 18 it is handled.In 15 hours, dropwise again and reaction mixture was stirred 2 hours in-78 ℃.Reaction is warming up to 0 ℃, and suppresses with saturated potassium sodium tartrate solution, tell organic layer, water layer extracts with 3 * 30 milliliters of ethers.With 3 * 30 milliliters of rare potassium sodium tartrate solutions, 3 * 30 milliliters of salt solutions wash with the organic layer that merges.Organic layer is through Na 2SO 4Drying is filtered, and in vacuum concentration, makes 9.5 gram (54.5%) glassy yellow oil and is diamines.
1H NMR（300MHz，CDCl 3）：delta6.9-6.75（m，3H），4.45（m，1H），3.8（s，3H），3.4（m，1H），2.85（m，2H），2.32（s，3H），2.2-1.4（m，12H）。
Example 20
1-methyl-5-(outside the 3-(-dicyclo (2.2.1) suffering-2-base oxygen)-the 4-p-methoxy-phenyl)-the 2-imidazolone
Get the aryl diamine that example 19 makes (0.95 gram, 3.14 mmoles) and be dissolved in 30 milliliters of anhydrous tetrahydro furans, use N, N '-carbonyl dimidazoles (0.76 gram, 4.71 mmoles) processing.Reacted on stirring at room 18 hours, then with 30 ml waters and 30 milliliters of vinyl acetic monomer dilutions.Divide water-yielding stratum, and with 2 * 20 milliliters of ethyl acetate extractions, with the organic layer that merges with 2 * 20 milliliters of 1N NaOH solution, 2 * 20 milliliters of 1N HCl, 2 * 20 ml waters and 2 * 20 salt solutions in the least wash.Organic layer is through Na 2SO 4Drying is filtered, and gets white slurry in vacuum concentration.With 3 * 50 milliliters of ether development purifying, the white solid that makes 214 milligrams (20.6%) is an imidazolone.Fusing point: 145-147 ℃.
1H NMR（300MHz，CDCl 3）：delta6.9-6.7（m，3H），4.5-4.3（m，2H），3.83（s，3H），3.7（m，1H），3.24（m，1H），2.62（s，3H），2.3（m，1H），2.05（m，1H），1.8-1.3（m，10H）。
C 19H 26N 2O 3Molecular weight calculated value: 330.1943.
HRMS(M+) molecule measuring definite value: 330.1962
Example 21
5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-2, the 4-imidazolone
Get 3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-methoxybenzaldehyde (20.0 grams, 81.3 mmole), sodium cyanide (8.0 grams, 162.6 mmoles) and volatile salt (32.0 grams, 333.3 mmoles) are dissolved in 100 milliliters of ethanol and 100 ml waters and refluxed 4 hours.With the reaction mixture cooling, with the neutralization of 1N HCl solution, product ethyl acetate extraction secondary, the organic layer water of collection, the salt solution washing is in vacuum concentration.The gained solid is dissolved in vinyl acetic monomer again, through Na 2SO 4Drying, in vacuum concentration, with the raw oil that obtains, with the crystallization glycolylurea of ether development generation 18.3 grams (71%), product is to 7 of cycloalkyl isomer; 3 inside/outside mixtures.
1H NMR（300MHz，DMSO）：delta7.4-6.8（m，3H），5.3（m，1H），4.7（m，.7H），4.3（m，.3H），3.9（s，3H），2.6-1.0（m，10H）。
C 17H 20N 2O 4Molecular weight calculated value: 316.1450
HRMS molecule measuring definite value: 316.1433
Example 22
4-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-2, the 4-imidazolone
Get example 21 2,4-imidazolone (3.0 grams, 9.5 mmoles) is dissolved in 40 milliliters of THF, with the solution-treated of 19 milliliters 1 mole lithium aluminum hydride in THF.With reaction mixture refluxed 48 hours, cooling also suppressed with the saturated solution of 10 milliliters of Seignette salts.The ethyl acetate extraction secondary is used in reaction, through dried over mgso, filters, and concentrates also fast through SiO 2Post is made elutriant with hexane vinyl acetic monomer (1: 1) → 20% ethanol/hexane.Obtain 610 milligrams of (21.2%) crystalline solid products.Product is an isomer in 75%.
Fusing point: 146-148 ℃
1H NMR（300MHz，CDCl 3）：delta6.8（m，3H），5.2（m，2H），4.8（m，1H），4.6（m，.7H），4.2（m，.3H），3.9（bs，3H），3.8（m，1H），3.3（m，1H），2.7-1.0（m，10H）。
C 17H 22N 2O 3Molecular weight calculated value: 302.1630
HRMS molecule measuring definite value: 302.1641
Ultimate analysis:
Calculated value: C, 67.52; H, 7.34; N, 9.27.
Measured value: C, 67.37; H, 7.30; N, 9.19.
Example 23
In α-N-methylamino--3-(-ring (3.3.1.1 3,7)-last of the ten Heavenly stems-2-base oxygen)-the 4-p-methoxybenzeneacetonitrile
Get 2-adamantyl isovanillin ether (5.29 grams that preparation DD gets, 18.5 mmole) be dissolved in 150 milliliters of ethanol, use sodium cyanide) 1.36 grams, 27.74 mmoles) and methylamine hydrochloride (1.83 grams, 27.74 mmole) handle, make reaction mixture even to wherein adding 20 ml waters.Reaction mixture in stirring at room 48 hours, with 300 milliliters of ether dilutions, is washed with 3 * 100 ml waters.Organic layer is through Na 2SO 4Drying is filtered and vacuum concentration, and making 5.28 gram (88%) viscous oils is amino-nitrile.
1H NMR（300MHz，CDCl 3）：delta7.0-6.75（m，3H），4.6（bs，1H），4.35（bs，1H），3.8（s，3H），2.5（bs，3H），2.3-1.4（m，14H）。
Example 24
2-methylamino--2-(-three ring (3.3.1.1 in the 3-( 3,7)-last of the ten Heavenly stems-2-base oxygen)-the 4-p-methoxy-phenyl) ethylamine
Get amino-nitrile (5.95 grams that get from example 23,18.25 mmole) be dissolved in 200 milliliters of dry toluenes, and this solution added-78 ℃ Dibal-H(91.25 mmole) in the solution of 270 milliliters of dry toluenes, reaction mixture was stirred 4 hours in-78 ℃.Remove cooling bath, dropwise add Seignette salt saturated solution inhibited reaction lentamente, reaction mixture rises to room temperature and dilutes with 500 milliliters of vinyl acetic monomers, water layer and organic layer are separated, water layer is with 1 * 100 milliliter of dichloromethane extraction, collected organic layer, with 1 * 100 milliliter of Seignette salt saturated solution and 2 * 100 milliliters of salt solution washings, organic layer is through K 2CO 3Drying is filtered, and makes 6.0 gram (～100%) clear, viscous oil in vacuum concentration and is adamantyl isovanillin diamines.
1H NMR（300MHz，CDCl 3）：delta6.9-6.7（m，3H），4.4（bs，1H），3.85（s，3H），3.35（m，1H），2.8（m，2H），2.3（s，3H），2.2-1.4（m，14H）.
Example 25
1-methyl-5-(-three ring (3.3.1.1 in the 3-( 3,7) last of the ten Heavenly stems-2-base oxygen)-4-p-methoxy-phenyl-2-imidazolone
The diamines of example 24 (6.0 grams, 18.2 mmoles) is dissolved in 180 milliliters of tetrahydrofuran (THF)s and use N, and the processing of N-carbonyl dimidazoles was in stirring at room 24 hours.Reaction mixture is diluted with 250 milliliters of ether and 200 ml waters.Organic layer is with 1 * 100 milliliter of 0.5N NaOH solution, 1 * 100 milliliter of 0.5N HCl solution, and 1 water washing is through Na 2SO 4Drying is filtered, in vacuum concentration.Resistates is through SiO 2Chromatography is made elutriant with 50% vinyl acetic monomer/hexane.Collect suitable part, it is the adamantyl imidazolone that vacuum concentration makes 1.85 gram (28%) white crystals groups.Fusing point: 180.5-181 ℃.
1H NMR（300MHz，CDCl 3）：delta6.8（bs，2H），5.4（bs，1H），4.45（m，2H），3.82（s，3H），3.66（m，1H），3.18（m，1H），2.57（s，3H），2.4-1.5（m，14H）.
HRMS 356.2115（M+）calcd.forC 21H 28N 2O 3356.2100.
C 21H 28N 2O 3Molecular weight calculated value: 356.2100
HRMS(M+) molecule measuring definite value: 356.2115
Example 26
α-N-ethylamino-3-(dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxybenzeneacetonitrile
Get 3-(dicyclo (2.2.1) that example 1 obtains heptan-2-base oxygen)-4-methoxybenzaldehyde (2.3 grams, 9.35 mmoles) is dissolved in 60 milliliters of ethanol, with sodium cyanide (0.60 gram, 12.2 mmoles) and the processing of hydrochloric acid ethylamine.Solution was even with 4 ml waters, in stirring at room 48 hours.Reaction mixture is with 250 milliliters of ether and 20 milliliters of saturated NaHCO 3Solution dilution, organic layer are with 3 * 100 ml waters, and Na is used in 3 * 100 milliliters of salt solutions washings 2SO 4Drying is filtered, and making 2.3 gram (82%) yellow viscous oils in vacuum concentration is the ethylamino nitrile.Product is 7: 3 mixtures to the inside/outside isomer of cycloalkyl ethers bonding.
1H NMR（300MHz，CDCl 3）：delta6.9-6.7（m，3H），4.6（bs，1H），4.55（m，7H），4.1（m，3H），3.7（s，3H），2.8-1.0（m，15H）。
Example 27
2-ethylamino-2-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) ethylamine
Get the ethylamino nitrile that example 26 obtains (2.3 grams, 7.7 mmoles) and be dissolved in 70 milliliters of dry toluenes, and this solution is added-78 ℃ Dibal-H(38.5 mmole) in the solution of 100 milliliters of toluene.Reaction mixture was stirred 2 hours in-78 ℃, be warming up to-40 ℃ again, come inhibited reaction with 60 milliliters Seignette salt saturated solution this moment lentamente, then reaction mixture risen to room temperature, dilutes with 200 milliliters of ether.Layering, water layer is washed the organic layer of inhaling collection 3 times with potassium sodium tartrate solution with 100 milliliters of vinyl acetic monomer re-extracts, with 2 * 100 ml waters, 3 * 100 milliliters of salt solution washings, footpath Na 2SO 4Drying is filtered, and in vacuum concentration, making 1.9 gram (81.2%) brown oils is diamines.7: 3 inside/outside compounds of isomer that product contains for the bicyclic alkyl ehter bond.
1H NMR（300MHz，CDCl 3）：delta6.85-6.7（m，3H），4.6（m，.7H），4.2（m，.3H），3.8（bs，3H），3.65（bs，1H），3.5（m，1H），2.8（m，2H），2.7-1.0（m，15H）。
Example 28
1-ethyl-5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-the 2-imidazolone
Get example 27 ethyl-diamines (1.8 grams, 5.9 mmoles) be dissolved in 20 milliliters of anhydrous tetrahydro furans, use N, N-carbonyl dimidazoles (1.4 grams, 8.8 mmoles) processing was in stirring at room 24 hours.Reaction mixture dilutes with 100 ml waters, and with 2 * 100 milliliters of ethyl acetate extractions, the organic layer of collection is with 2 * 50 milliliters of 0.5N NaOH solution, 2 * 50 milliliters of 0.5N HCl solution, and 1 * 50 ml water and 2 * 50 milliliters of salt solutions washings, organic layer is through Na 2SO 4Drying is filtered, and in vacuum concentration, the oil that obtains is developed with ether, and with the ether washing, making 579 milligrams of (29.7%) white solids in vacuum-drying is imidazolone.Product is 7: 3 inside/outside mixtures of the isomer that contains of bicyclic alkyl ehter bond.Fusing point 149-153 ℃.
1H NMR（300MHz，CDCl 3）：delta6.8-6.7（m，3H），5.4-5.1（bs，1H），4.55（m，1.7H），4.15（m，.3H），3.8（s，2.1H），3.77（s，.7H），3.6（m，1H），3.4（m，1H），3.2（m，1H），2.72（m，1H），2.54（m，.7H），2.45（m，.3H），2.27（m，.3H），2.23（m，.7H），2.0（m，2H），1.8-1.1（m，6H），.98（bt，3H，J＝7Hz）.
C 19H 26N 2O 3Molecular weight calculated value: 330.1943
HRMS(M+) molecule measuring definite value: 330.1951
Example 29
α-N-allyl amino-3-(dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxybenzeneacetonitrile
Get 3-(dicyclo (2.2.1) that example 1 obtains heptan-2-base oxygen)-4-methoxybenzaldehyde (2.3 grams, 9.35 mmole) be dissolved in 60 milliliters of ethanol, with sodium cyanide (0.60 gram, 12.2 mmoles), allyl amine (0.9 milliliter, 12.2 mmoles) and 1.02 milliliters of dense HCl solution-treated.Reaction mixture stirred 48 hours in the chamber, with 250 milliliters of ether and 20 milliliters of saturated NaHCO 3Solution dilution.Organic layer is with 3 * 100 ml waters, and 3 * 100 milliliters of salt solutions washings through dried over sodium sulfate, are filtered, and vacuum concentration makes 2.7(92%) the viscosity yellow oil is allyl group cyano group amine.Product is 7: 3 inside/outside mixtures of the isomer of bicyclic alkyl ether linking.
1H NMR（300MHz，CDCl 3）：delta6.9-6.6（m，3H），5.75（m，1H），5.18（bd，1H，J＝15Hz），5.07（bd，1H，J＝9Hz），4.6（bs，1H），4.5（m，.7H），4.07（m，.3H），3.7（s，3H），3.4-3.2（m，2H），2.6-1.0（m，10H）。
Example 30
2-allyl amino-2-(3-dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) ethylamine
Get the allyl amino mixture of nitriles that example 29 obtains and be dissolved in 80 milliliters of dry toluenes, this solution is dropwise added-78 ℃ of Dibal-H(43 mmoles) in the solution of 110 milliliters of dry toluenes, reaction mixture was stirred 2 hours in-78 ℃, slowly be warming up to-40 ℃, come at leisure inhibited reaction with 70 milliliters of Seignette salt saturated solutions this moment.Then reaction is risen to room temperature,, water layer and organic layer are separated with 250 milliliters of ether dilutions, water layer is with 150 milliliters of vinyl acetic monomer re-extracts, and organic room of collection is with 3 * 50 milliliters of potassium sodium tartrate solutions, 2 * 100 ml waters, 3 * 100 milliliters of salt solution washings, footpath Na 2SO 4Drying is filtered, and in vacuum concentration, making 2.4 gram (88.3%) light brown viscous oils is the allyl group diamines.Product is 7: 3 inside/outside mixtures of the isomer of bicyclic alkyl ether linking.
1H NMR（300MHz，CDCl 3）：delta6.85-6.7（m，3H），5.8（m，1H），5.08（bd，J＝15Hz），5.01（bd，J＝9Hz），3.73（s，3H），3.5（m，1H），3.1（m，2H），2.75（m，2H），2.6-1.0（m，10H）。
Example 31
1-allyl group-5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-the 2-imidazolone
Get example 30 allyl group two amine mixt (2.3 grams, 7.3 mmoles) be dissolved in 30 milliliters of anhydrous tetrahydro furans, use N, the processing of N-carbonyl dimidazoles was in stirring at room 24 hours.Reaction mixture dilutes with 100 ml waters, with 2 * 100 milliliters of ethyl acetate extractions.The organic layer of collecting is with 2 * 50 milliliters of 0.5N NaOH solution, 2 * 50 milliliters of 0.5N HCl solution, and 1 * 50 ml water and 2 * 50 milliliters of salt solutions wash, and organic layer is through Na 2SO 4Drying is filtered, and in vacuum concentration, the oil that obtains is developed with ether, and with the ether washing, in vacuum-drying, making 739 milligrams of (29.6%) white solids is allyl imidazole quinoline ketone.Product is 7: 3 inside/outside mixtures of the isomer of bicyclic alkyl ether linking.Fusing point: 110-113 ℃.
1H NMR（300MHz，CDCl 3）：delta6.8-6.65（m，3H），5.6（m，1H），5.06（bd，1H，J＝9Hz），4.98（bd，1H，J＝15Hz），4.6（m，1.7H），4.1（m，1.3H），3.8（s，3H），3.7（m，1H），3.28（m，1H），3.1（dd，1H，J＝12Hz，H＝8Hz），2.57（m，.7H），2.48（m，.3H），2.3-2.2（m，1H），2.1-1.1（m，8H）。
C 20H 26N 2O 3Molecular weight calculated value: 342.1943
HRMS(M +) the molecule measuring definite value: 342.1971
Example 32
α-N-styroyl amino-3-(dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxybenzeneacetonitrile
Get norborneol isovanillin (2.3 grams, 9.35 mmoles) and be dissolved in 60 milliliters of ethanol, with sodium cyanide (0.60 gram, 12.2 mmoles), phenylethylamine (1.5 milliliters, 12.2 mmoles) and 1.02 milliliters of concentrated hydrochloric acid solutions are handled.With reaction mixture with 250 milliliters of ether and 20 milliliters of saturated NaHCO solution dilutions, organic layer washs with 3 * 100 ml waters, 3 * 100 milliliters of salt solutions, through dried over sodium sulfate, filter, it is the styroyl amino-nitrile that vacuum concentration gets 3.6 gram (～100%) viscosity yellow oils.Product is 7: 3 mixtures of the isomer of dicyclo (2.2.1) heptan-2-base ether linking.
1H NMR（300MHz，CDCl 3）：delta7.4-7.1（m，5H），6.9-6.7（m，3H），4.65（bs，1H），4.55（m，.7H），4.1（m，.3H），3.78（bs，3H），3.1-2.5（m，5H），2.3-1.0（m，9H）.
Example 33
2-styroyl amino-2-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) ethylamine
Get the benzene ethylamino mixture of nitriles that example 32 obtains (3.6 grams, 9.4 mmoles) and be dissolved in 90 milliliters of dry toluenes, this solution is dropwise added-78 ℃ of diisobutyl alanates (47 mmole) in 120 milliliters toluene solution.React on-78 ℃ and stirred 2 hours, slowly be warming up to-40 ℃, 70 milliliter come at leisure inhibited reaction with the Seignette salt saturated solution this moment.Then reaction is risen to room temperature,, water layer and organic layer are separated with 250 milliliters of ether dilutions, water layer extracts repeatedly with 200 milliliters of vinyl acetic monomers, and the organic layer of collection is dissolved in 3 * 50 milliliters of Seignette salts, 2 * 100 ml waters, 3 * 100 milliliters of salt solution washings are through Na 2SO 4Drying is filtered, and in vacuum concentration, making 3.4 gram (95%) little brown viscous oils is the styroyl diamines.Product is 7: 3 inside/outside mixtures of the isomer of bicyclic alkyl ether linking.
1H NMR（300MHz，CDCl 3）：delta7.4-7.1（m，5H），6.9-6.7（m，3H），4.6（m，.7H），4.2（m，.3H），3.8（bs，3H），3.7（bs，1H），3.55（m，1H），3.1-2.5（m，7H），2.5-1.0（m，9H）.
Example 34
1-styroyl-5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-the 2-imidazolone
The styroyl diamines inside/outside mixture (3.3 grams, 8.7 mmoles) of getting example 33 is dissolved in 40 milliliters of anhydrous tetrahydro furans, uses N, N '-carbonyl dimidazoles is handled, in stirring at room 24 hours, reaction mixture is diluted with 100 ml waters, with 2 * 100 milliliters of ethyl acetate extractions.The organic layer of collecting is with 2 * 50 ml waters, 0.5N NaOH solution, and 2 * 50 milliliters of 0.5N HCl solution, 1 * 50 ml water and 2 * 5 milliliters of salt solutions wash.Organic layer is through Na 2SO 4Drying is filtered, and in vacuum concentration, resistates is through flash chromatography chromatography (32-60SiO 2, 50% vinyl acetic monomer/hexanaphthene → 100% vinyl acetic monomer).In vacuum concentration, with the ether development, obtaining 337 milligrams of (10.6%) white solids is the styroyl imidazolone with suitable part.Product is 7: 3 inside/outside mixtures of the isomer of bicyclic alkyl ether linking.
Fusing point: 151-154 ℃
1H NMR（300MHz，CDCl 3）：delta7.4-7.1（m，5H），6.9-6.7（m，3H），4.9（bs，1H），4.6（m，.7H），4.45（m，1H），4.2（m，.3H），3.83（bs，3H），3.7（m，2H），3.26（m，1H），3.1-2.5（m，4H），2.4-1.1（m，9H）。
C 25H 30N 2O 3Molecular weight calculated value: 406,2257
HRMS(M+) molecule measuring definite value: 406.2294
Example 35
4-(in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-methoxyphenyl) imidazole hydrochloride
Get in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl glyoxal reaction thing (0.30 gram, 1.03 mmoles) and CH 2The O aqueous solution (3 milliliter 37% the aqueous solution) is dissolved in 3 milliliters of ethanol, and adds 3 milliliters of dense NH 4OH.Reaction mixture comes inhibited reaction in stirring at room 1.5 hours with 20 ml waters, and reaction mixture mixes the organic layer that merges with ethyl acetate extraction 2 times, regulate pH to 2, divide water-yielding stratum, alkalize to pH9 with 50%NaoH, water layer ethyl acetate extraction 3 times, organic layer washes with water, through MgSO 4Drying is filtered, and gets 0.2 gram buttery imidazoles in vacuum concentration.This oil is dissolved in 1 milliliter of acetone also with 2 milliliters of acetone treatment that HCl is saturated.Solution is handled with ether, collecting precipitation, obtain 0.12 the gram (68.4%) imidazoles hydrochloride.
Fusing point 201-202 ℃ (decomposition)
1H NMR（300MHz，CDCl 3）：delta6.9-6.7（m，4H），6.45（m，1H），4.2（m，1H），4.5（s，3H），2.2（m，1H），1.87（m，1H），1.8-.7（m，9H）.
C 19H 20N 2O 3Molecular weight calculated value: 284,1525
HRMS(M+) molecule measuring definite value: 284.1515
Example 36
Press example 2 operation with 3-(1,2-indane-2-base oxygen)-4-methoxybenzaldehyde (2.25 grams, 839 mmoles) is converted into amino-nitrile (2.36 grams, 91.3%).
1H NMR（300MHz，CDCl 3）：delta7.3-7.05（m，6H），6.85（m，1H），5.2（m，1H），4.7（bs，1H），3.8（s，3H），3.45（dd，2H，J＝13Hz，J＝7Hz），3.25（dd，2H，J＝13Hz，J＝3Hz），2.6（s，3H）.
Example 37
2-methylamino--2-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl) ethylamine
Get the amino-nitrile (2.25 gram) of example 36,7.3 mmoles) the operation reduction of press example 3, give birth to the transparent viscous oil of diamines (1.5 restrain 65.5%).
1H NMR（300MHz，CDCl 3）：delta7.3-7.1（m，4H），6.9（m，3H），5.25（m，1H），3.8（s，3H），3.5（m，1H），3.45（dd，2H，J＝13Hz，J＝7Hz），3.25（dd，2H，J＝13Hz，J＝3Hz），2.87（m，2H），2.4（bs，3H）。
Example 38
1-methyl-5-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl)-the 2-imidazolone
The diamines (1.50 gram, 4.8 mmoles) of getting example 37 is converted into imidazolone (126 milligrams, 37 mmoles) by the operation of example 4.
1H NMR（300MHz，CDCl 3）：delta7.3-7.2（m，4H），6.9（m，3H），5.3-5.2（m，1H），5.0（bs，1H），4.54（m，1H），3.9（s，3H），3.78（m，1H），3.45（dd，2H，J＝13Hz，J＝7Hz），3.3（m，1H），3.25（dd，2H，J＝13Hz，J＝3Hz），2.75（s，3H）.
Example 39
α-N-methylamino--3-(outer-three ring (3.2.1.0 2,6)-last of the ten Heavenly stems-8-base oxygen base)-the 4-p-methoxybenzeneacetonitrile
Get outer-three ring (3.2.1.0 of 3- 2,6) last of the ten Heavenly stems-8-base oxygen)-4-p-methoxybenzaldehyde thing (1.28 grams, 4.47 millimoles) is dissolved in 60 milliliters of ethanol, with sodium cyanide (274 milligrams, 5.6 millimoles) and methylamine hydrochloride (370 milligrams, 5.6 mmoles) processing.To make reaction be homogeneous to wherein adding 20 ml waters, with reaction mixture in stirring at room 20 hours, with 250 milliliters of ethers dilutions, with 2 * 100 ml waters, 1 * 100 milliliter of pH7 phosphate buffered saline buffer, 1 * 100 milliliter of salt solution washs, through Na 2SO 4Drying is filtered, and in vacuum concentration, making 1.13 gram (78%) viscous oils is the first cyanamide.
1H NMR（300MHz，CDCl 3）：delta 7.0-6.7（m，3H），4.2（m，2H），3.8（s，3H），2.55（s，3H），2.3-.8（m，14H）.
Following compounds prepares from suitable reactant with similar approach:
-three ring (3.2.1.0 in α-N-methylamino--3-( 2,6)-last of the ten Heavenly stems-8-base oxygen)-the 4-p-methoxybenzeneacetonitrile, yield 89.4%
1H NMR（300MHz，CDCl 3）：delta7.1-6.81（m，3H），4.7（bs，1H），4.6（m，1H），3.9（s，3H），2.6（s，3H），2.8-1.0（m，14H）。
Example 40
2-methylamino--2-(outer-three ring (3.2.1.0 of 3-( 2,6) last of the ten Heavenly stems-8-base oxygen)-the 4-p-methoxy-phenyl) ethylamine
The title compound first cyanamide (1.94 grams, 5.95 mmoles) of getting example 39 is dissolved in 60 milliliters of dry toluenes, this solution is added in 150 milliliters of toluene solutions of-78 ℃ of diisobutyl alanates (29.75 mmole).After finishing, reaction mixture in-78 ℃ of stirrings 4 hours, is come inhibited reaction with 65 milliliters of Seignette salt saturated solutions then.Reaction slowly rises to room temperature, with the ether dilution, tells organic layer, and residual water layer is saturated with NaCl, with 2 * 100 milliliters of ethyl acetate extractions.With the organic layer of collecting, with 1 * 100 milliliter of saturated Seignette salt, 1 * 100 milliliter of salt solution washing is through K 2CO 3Drying is filtered, and in vacuum concentration, making 1.8 gram (92%) yellow viscous oils is the outer isomer of diamines.
1H NMR（300MHz，CDCl 3）：delta6.85-6.65（m，3H），4.15（m，1H），3.75（s，3H），3.38（m，1H），2.8（m，2H），2.3（s，3H），2.4-.8（m，14H）.
Use similar approach, from the interior-methylamino-nitrile isomer of example 39 prepare above-mentioned in-isomer.
1H NMR（300MHz，CDCl 3）：delta7.0-6.8（m，3H），5.7（m，1H），3.9（s，3H），3.5（m，1H），3.0-1.0（m，19H）.
Example 41
1-methyl-5-(outer-three ring (3.2.1.0 of 3-( 2,6) last of the ten Heavenly stems-8-base oxygen)-the 4-methoxyphenyl)-the 2-imidazolone
Get title compound diamines 91.8 gram of example 40,5.45 mmoles) be dissolved in 125 milliliters of tetrahydrofuran (THF)s, use N, N '-carbonyl dimidazoles processing was in stirring at room 40 hours.Reaction mixture is diluted with 300 milliliters of ethers, with 2 * 100 ml waters, 1 * 0.5N NaoH, 1 * 0.5N HCl, 1 * 100 ml water and 1 * 100 milliliter of salt solution washing.Organic layer is through Na 2SO 4Dry in vacuum concentration.Resistates is through SiO 2(32-64) flash chromatography is made elutriant with 50% vinyl acetic monomer/hexane.In vacuum concentration, making 625 milligrams of (32%) white solids is imidazolone (interior-isomer) with suitable part.Fusing point, 168-170 ℃.
Ultimate analysis:
C 21H 28N 2O 3Calculated value: C, 70.76; H, 7.92; N, 7.86.
Measured value: C, 70.54; H, 7.92; N, 7.97.
1H NMR（300MHz，CDCl 3）：delta6.85-6.7（m，3H），5.15（bs，1H），4.4（m，1H），4.12（m，1H），3.81（s，3H），3.68（m，1H），3.22（m，1H），2.6（s，3H），2.3-.8（m，14H）。
C 21H 28N 2O 3Molecular weight calculated value: 356.2100
HRMS(M+) molecule measuring definite value: 356.2155
Use similar approach, prepare isomery tricyclic alkyl ether, yield 20.7% from the diamines of example 40 isomer.
Fusing point: 149-152 ℃
1H NMR（300MHz，CDCl 3）：delta6.9-6.8（m，3H），5.15（bs，1H），4.65（m，1H），4.5（m，1H），3.9（s，3H），3.75（m，1H），3.25（m，1H），2.7（s，3H），2.8-1.0（m，14H）。
C 21H 28N 2O 3Molecular weight calculated value: 356.2099.
HRMS molecule measuring definite value: 356.2120
Ultimate analysis:
C 21H 28N 2O 3Calculated value: C, 70.76; H, 7.92; N, 7.86.
Measured value: C, 70.72; H, 7.86; N, 7.79.
Example 42
-three ring (3.2.1.0 in α-N-methylamino--3-( 2,6)-last of the ten Heavenly stems-4-base oxygen)-the 4-p-methoxybenzeneacetonitrile
Press the step of example 39, prepare amino-nitrile, yield 95.4% from corresponding three ring isovanillin ethers.
1H NMR（300MHz，CDCl 3）：delta7.0-6.7（m，3H），4.7（m，1H），4.65（bs，1H），3.87，3.85（s，3H），[2-methoxyls]，2.5（bs，3H），2.2-8.5（m，14H）。
Example 43
2-methylamino--2-(-three ring (3.2.1.0 in the 3-( 2,6)-last of the ten Heavenly stems-4-base oxygen)-the 4-p-methoxy-phenyl) ethylamine
Press the step of example 40, prepare diamines from the amino-nitrile of example 42.
1H NMR（300MHz，CDCl 3）：delta6.8-6.7（m，3H），4.75（m，1H），3.78（s，1H），3.38（m，1H），2.8（m，2H），2.3（s，3H），2.4-.9（m，14H）。
Example 44
1-methyl-5-(-three ring (3.2.1.0 in the 3-( 2,6) last of the ten Heavenly stems-4-base oxygen)-the 4-methoxyphenyl)-the 2-imidazolone
Press the step of example 41, prepare imidazolone, yield 7.2% from the diamines of example 43.
1H NMR（300MHz，CDCl 3）：delta6.8-6.7（m，3H），5.75（bs，1H），4.75（m，1H），4.42（m，1H），3.83（s，3H），3.72（m，1H），3.28（m，1H），2.65（s，3H），2.3-.9（m，14H）。
13C NMR（75.4MHz，CDCl 3）：delta163.2，150.8，147.8，131.8，120.0，114.5，112.4，82.5，62.8，56.2，47.6，46.2，40.4，37.7，31.8，28.8，28.5（17lines）。
Ultimate analysis:
Measured value: C, 69.74, H, 7.93, N, 7.48
Calculated value: C, 70.75, H, 7.91, N, 7.86
Example 45
α-formyl radical-(3-(is outer-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-methoxyphenyl) acetonitrile
Get the nitrile (1.2 grams, 4.6 mmoles) and the ethyl formate (2 milliliters) that obtain from preparation R and be dissolved in 10 milliliters of benzene, in this solution, add sodium hydride (50% in oil) (0.39 gram, 8.2 mmoles) in batches.Reaction is warming up to 40 ℃ to be kept 1.5 hours.Dilute with the reaction mixture cooling and with 3 milliliters of ethanol and 20 milliliters of hexanes.Collecting precipitation is suspended in it in water, and with 1N HCl acidifying, product is with 3 * 20 milliliters of ethyl acetate extractions, and extract is washed with salt, filters, and in vacuum concentration, making 0.62, to restrain (47%) thickness yellow oil be the formylation compound.
1H NMR（300MHz，CDCl 3）：delta7.4-6.7（m，4H），4.25（m，1H），4.25（m，1H），3.8（s，3H），2.6-1.0（m，10H）。
Use similar approach; prepare following α-formyl radical prussiate from suitable precursor Bian Jiqing compound derivative: acetonitrile α-formyl radical-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl); yield 68.2%, be in: the mixture of outer (7: 3) isomer
1H NMR（300MHz，CDCl 3+CD 3OH）：delta7.2-7.0（m，2H），6.65（m，2H），4.5（m，.7H），4.1（m，.3H），3.7（bs，3H），2.6-1.0（m，10H）;
α-formyl radical-(3-(1,2-indanyl-2-base oxygen)-4-p-methoxy-phenyl)-and acetonitrile, yield 60%.
1H NMR（300MHz，CDCl 3）：delta7.8（m，1H），7.3（m，1H），7.2-7.1（m，4H），6.9（m，3H），5.15（m，1H），3.8+3.77（s，3H），3.4-3.1（m，4H）;
α-formyl radical-(in the 3--dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl) acetonitrile, yield 71.8%.
1H NMR（300MHz，CDCl 3）：delta7.3-7.1（m，2H），6.8（m，3H），4.6（m，1H），3.9（s，3H），2.6-1.0（m，10H）。
Example 46
The alpha-amino group methylene radical-(3-(is outer-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl) acetaldehyde
With the excessive Raney's nickel that washed with water; in 20 milliliters of ethanolic solns of the title compound formylation compound that adding obtains from embodiment 45 (0.53 gram, 1.81 moles), reaction mixture hydrogenation 7 hours under 40 pounds of/inch pressure; through diatomite filtration, then wash with ethanol.Filtrate makes 0.47 gram (89.9%) oily aldimine in vacuum concentration.Product is the mixture of aldimine and enamine aldehyde.
1H NMR（300MHz，CDCl 3）：delta9.6（d，J＝4Hz）+9.1（bs）（1H），7.2-6.6（m，4H），5.1（bs，1H），4.2（m，1H），3.85（s，3H），2.6-1.0（m，10H）。
Following compounds can prepare with similar method with the reactant of suitable tautomers mixture:
7: 3 mixtures of inside/outside isomer of alpha-amino group methylene radical-(in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-4-anisole ethylhexanal, yield 83.3%.
The alpha-amino group methylene radical-(in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl) acetaldehyde, yield 84%.
1H NMR（300MHz，CDCl 3）：delta9.5+9.0（bs，1H），6.9（m，3H），5.4（bs，1H），4.6（m，1H），3.8（s，3H），2.6-1.0（m，10H）;
Alpha-amino group methylene radical-(3-(1,2-indanyl-2-base oxygen)-4-p-methoxy-phenyl) acetaldehyde, yield 84.6%.
1H NMR（300MHz，CDCl 3）：delta9.5+9.0（bs，1H），7.2-7.1（m，4H），6.9（m，3H），5.3（bs，1H），5.1（bs，1H），3.8（s，3H），3.1（m，4H）。
Example 47
5-(3-) is outer-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl)-the 2-pyrimidone
The aldimine (0.47 gram, 1.63 mmoles) of getting example 46 is dissolved in 5 milliliters of ethanol, with 1 milliliter of concentrated hydrochloric acid and urea (0.12 gram, 1.95 mmoles) processing, with reaction mixture temperature rising reflux 1.5 hours.With the reaction mixture cool to room temperature, use NH 4Sharp in the OH aqueous solution, with 6 * 10 milliliters of ethyl acetate extractions.The organic layer that merges is through MgSO 4Drying is filtered, and is concentrated into driedly, and making 2 gram crystallized products is pyrimidone (yield 39.3%).
Fusing point: 195-196 ℃
1H NMR（300MHz，CDCl 3）：delta8.4（m，2H），6.9-6.7（m，4H），4.2（m，1H），3.82（s，3H），2.5-.9（m，10H）。
C 18H 20N 2O 3Molecular weight calculated value: 312.1474
HRMS(M+) molecule measuring definite value: 312.1472
Similarly, can prepare following compounds from suitable precursor enamine aldehyde:
5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-and the 2-pyrimidone, be 7: 3 inside/outside isomer mixtures, yield 60.3%.
1H NMR（300MHz，CDCl 3）：delta8.4（m，2H），6.9-6.7（m，4H），4.65（m，.7H），4.25（m，.3H），3.85（bs，3H），2.7-1.1（m，10H）;
5-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl)-1,2 dihydropyrimidinonesand, yield 13.9%.
1H NMR（300MHz，CDCl 3）：delta8.6（bs，2H），7.3-7.0（m，7H），5.35（m，1H），3.75（s，3H），3.4-3.0（m，4H）;
5-(in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl)-1,2-dihydropyrimidinonesand, yield 47%.
Fusing point: 220 ℃
1H NMR（300MHz，CDCl 3）：delta8.5（bs，2H），7.21（s，1H），6.9-6.8（m，3H），4.6（m，1H），3.85（s，3H），2.6-1.0（m，10H）。
Example 48
α-N-methylamino--4-methoxyl group-3-oil of mirbane acetonitrile
The step of pressing example 39 is from 4-methoxyl group-2-nitrobenzaldehyde (25.80 grams, 142.4 mmoles) preparation amino-nitrile, separate after filtration 31.20 gram products (yield 99%).
HNMR（90MHz，CDCl 3）：δ7.8-7.2（m，3H），5.0（bs，1H）。
Example 49
2-methylamino--2-(4-methoxyl group-3-nitrophenyl) ethylamine
Get example 48 amino-nitrile (15 grams, 67.81 mmoles) be dissolved in 150 milliliters of toluene, be cooled to-78 ℃.In this solution, add the Dibal-H(181 milliliter, 27.12 mmoles) the 1.5M toluene solution, react on-78 ℃ and stirred 3 hours, be warming up to 0 ℃, suppress with 150 ml waters.Reaction solution is regulated pH to 2 with 6N HCl, with 2 * 50 milliliters of ether washings.
The aqueous solution is regulated pH to 12 with 25%NaOH solution, with 3 * 100 milliliters of dichloromethane extractions, through the MgSO drying, filters, and concentrates in vacuum, makes 11.0 gram (72%) burgundy oil and is the nitro diamines.Product need not be further purified and can use.
Example 50
1-methyl-5-(4-methoxyl group-3-nitrophenyl)-the 2-imidazolone
Get the nitro diamines (11 grams, 48.88 mmoles) that obtains from example 49 and prepare nitroimidazole quinoline ketone, obtain 4.51 gram (yield 37%) little orange solids products by the step of example 40.
1H NMR（90MHz，CDCl 3）：delta7.7-7.0（m，3H），4.5（m，1H），3.9（s，3H），3.7（m，1H），3.2（m，1H），2.6（s，3H）。
Example 51
1-methyl-5-(3-amino-4-p-methoxy-phenyl)-the 2-imidazolone
Get platinum oxide (0.135 gram) and be suspended in 1 milliliter of concentrated hydrochloric acid, 30 ml methanol solution of the nitroimidazole quinoline ketone that adding example 50 obtains in this solution (4.51 grams, 17.95 mmoles).With methyl alcohol the reactant volume is added to 200 milliliters.Be placed on Pa Er jolting device (Parr Shaker), with 50 pounds/inch 2H 2Pressure hydrogenation 45 minutes, the elimination catalyzer, reaction solution obtains oil in vacuum concentration, and this oil is dissolved in vinyl acetic monomer again, with 1N NaoH solution washing, through MgSO 4Drying is filtered, and concentrates in vacuum, and the oil that obtains is crude product aniline, need not be further purified.
1H NMR（300MHz，CDCl 3）：delta6.7（m，3H），5.6（bs，1H），4.4（m，1H），3.8（s，3H），3.7（m，1H），3.2（m，1H），2.6（s，3H）。
Example 52
1-methyl-5-(3-(dicyclo (2.2.1) heptan-2-base is amino)-4-p-methoxy-phenyl)-the 2-imidazolone
The aniline (3.07 grams, 17.95 mmoles) of getting example 51 is dissolved in 60 milliliters of Glacial acetic acid and adds Norcamphor (2.37 grams, 21.54 mmoles) in this solution.Reaction mixture is cooled to 5 ℃, and adds sodium cyanoborohydride (1.36 grams, 21.54 mmoles), reactant is poured in the ice, regulate pH to 7 with 1N NaoH solution.The water layer dichloromethane extraction through the MgSO drying, filters, and gets brown oil in vacuum concentration, passes through the SiO post fast, makes elutriant with vinyl acetic monomer.Merge suitable part and get white paste,, obtain the product of 0.57 gram (yield 10%) white crystalline solid with the ether development in vacuum concentration.
Fusing point: 171-174 ℃
1H NMR（250MHz，CDCl 3）：delta6.75-6.5（m，3H），4.6（m，1H），4.4（m，1H），3.86（s，3H），3.7（m，1H），3.25（m，1H），2.65（s，3H），2.6-2.0（m，3H），1.8-1.2（m，6H），.85（m，1H）。
Ultimate analysis:
Calculated value: C, 68.03, H, 7.99, N, 13.37
Measured value: C, 68.98, H, 7.40, N, 13.41
C 18H 23N 3O 2Molecular weight calculated value: 315.1946
HRMS(M+) molecule measuring definite value: 315.1948
Example 53
4-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) pyrazoles
Get the suitable enamine aldehyde that example 46 obtains (0.20 gram, 0.697 mmole) and be dissolved in 5 milliliters of ethanol, with 0.2 milliliter of hydrazine processing.With reaction mixture refluxed 30 minutes, cooling, water suppresses.Product ethyl acetate extraction 2 times, the organic layer that washing merges is through MgSO 4Drying is filtered in vacuum concentration and is got yellow oil.The crystallization from vinyl acetic monomer of rough thing is folded, make the pyrazoles of 0.11 gram (55.3%) white crystalline solid.Product is 7: 3 inside/outside mixtures of norborneol ether linking.
Fusing point: 180-181 ℃
MP＝180-181℃。
1H NMR（30MHz，CDCl 3）：delta7.8（bs，2H），7.1-6.84（m，3H），4.7（m，.7H），4.3（m，.3H），3.86（bs，3H），2.8-1.0（m，10H）.
C 17H 2N 2O 2Molecular weight calculated value: 284.1525
HRMS(M+) molecule measuring definite value: 284.1531
Example 54
6-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) imidazoles (1.2-a) pyrimidine
Get the title compound enamine aldehyde (0.20 gram, 0.7 mmole) of example 46,2-aminooimidazole sulfonate (0.27 gram, 1 mmole) is dissolved in ethanol, handles with 0.5 milliliter of concentrated hydrochloric acid, refluxes 1 hour.With the reactant cooling, water suppresses, and uses ethyl acetate extraction 3 times, and the organic layer of merging washs with salt solution, through MgSO 4Drying is filtered, and in vacuum concentration, with crude product vinyl acetic monomer recrystallization, makes 0.20 gram (85.3%) cream-coloured crystalline solid compound.Product is 7: 3 inside/outside mixtures of bicyclic alkyl isomer.
Fusing point: 130 ℃ (decomposition)
1H NMR（300MHz，CDCl 3）：delta8.8（m，1H），8.5（m，1H），7.85（bs，1H），7.6（bs，1H），7.2-6.9（m，3H），4.75（m，7H），4.3（m，13H），3.9（bs，3H），2.8-1.1（m，10H）。
C 20H 21O 2N 3Molecular weight calculated value: 335.1633
HRMS molecule measuring definite value: 335.1610
Example 55
6-(3-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl)-pyrazoles (2.3-a) pyrimidine
Get title compound enamine aldehyde (0.20 gram of example 46,0.7 the milli mmole) and (83 milligrams of 3-amino-pyrazols, 1.0 mmole) be dissolved in 5 milliliters of ethanol, handle with 0.5 milliliter of dense HCl, with reaction mixture refluxed 30 minutes, be cooled to room temperature, water suppresses, with product ethyl acetate extraction 2 times.The organic layer that merges washs with salt solution, through MgSO 4Drying is filtered, and concentrates in vacuum.Crude product is folded from vinyl acetic monomer/hexane crystallization, make 0.180 gram (76.7%) crystalline solid product, product contains the inside/outside mixture of bicyclic alkyl resistates.
Fusing point: 136-137 ℃
1H NMR（300MHz，CDCl 3）：delta8.9（bs，1H），8.75（m，1H），8.15（m，1H），7.2-7.0（m，3H），6.8（m，1H），4.75（m，7H），4.3（m，.3H），3.9（bs，3H），2.8-1.1（m，10H）.
Example 56
3-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-2-ethoxycarbonyl ethyl propenoate
Get 3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-methoxybenzaldehyde (5.0 grams, 0.02 mmole), diethyl malonate (3.21 grams, 0.02 mole) and piperidines are dissolved in toluene and refluxed 15 hours.With the reaction mixture cooling, in vacuum concentration, the oil that obtains is dissolved in the vinyl acetic monomer.The saturated NH of organic layer 4Cl solution, water, the salt solution washing, drying is filtered in vacuum concentration, makes 6.56 gram (84.5%) diethyl ester products, and product is 7: 3 inside/outside mixture of isomers.
1H NMR（300MHz，CDCl 3）：delta7.6（m，1H），7.2-16.7（m，3H），4.5（m，.7H），4.4-4.1（m，5H），3.85（bs，3H），2.6-1.0（m，6H）。
Example 57
3-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-3-cyanopropionate
Diester (6.5 gram, 0.0167 mole) and the sodium cyanide (0.833 restrains 0.017 mole) of getting example 56 were dissolved in 75 milliliters of ethanol, in stirring at room 24 hours.Vacuum is removed ethanol, and between dividing between vinyl acetic monomer and the water, water layer extracts repeatedly with vinyl acetic monomer with the solid that obtains.Organic layer water that merges and salt solution washing are through MgSO 4Drying is filtered, and in vacuum concentration, makes 4.45 gram (77.8%) yellow oily cyano group esters, and product contains 7: 3 mixtures of inside/outside bicyclic alkyl isomer.
1H NMR（300MHz，CDCl 3）：delta6.9-6.75（m，3H），4.6（m，7H），4.45（m，1H），4.3（q，24，J＝5Hz），4.2（m，.3H），4.1（m，2H），3.85（s，3H），2.8-1.1（m，3H）.
Example 58
4-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-2-Pyrrolidone
Getting platinum oxide (400 milligrams) is suspended in 50 milliliters of acetic acid, in 50 pounds/inch 2Carried out hydrogenization under the pressure 1 hour.Get the cyano group ester (2.0 grams, 5.84 mmoles) that example 57 gets, add to PtO 2Be suspended in the solution of 50 milliliters of acetate, reaction mixture is at 50 pounds/inch 2H 2Hydrogenation is 18 hours under the pressure.Reaction mixture cleans with N, and in vacuum concentration, remaining acetate in minute carries out azeotropic with toluene in vacuum.The oil that obtains is dissolved in 50 milliliters of toluene, handles with 10 milliliters of triethylamines, refluxes 24 hours.Then with reaction mixture cooling,, and resistates is dissolved in vinyl acetic monomer in vacuum concentration.Organic layer 1N HCl, water, salt solution washing, MgSO 4Drying is filtered in vacuum concentration, gets α-carbonyl oxyethyl group lactan.Be dissolved in this lactan in the NaoH alcoholic solution and be back to the TLC(thin-layer chromatography) show till the noresidue ester.With the reaction mixture cooling, with 1N HCl neutralization, with acetic acid second sparrow hawk extraction 3 times.With the organic layer washing, drying is filtered and concentrated α-carboxylic acid, uses heating means in 180 ℃ of decarboxylations this carboxylic acid, and making 611 milligrams of (34.7%) white solids is pyrrolinone.Product is 7: 3 mixtures of inside/outside bicyclic alkyl isomer.
Fusing point: 153-156 ℃
1H NMR（300MHz，CDCl 3）：delta6.9-6.6（m，3H），4.6（m，.7H），4.2（m，.3H），3.85（bs，3H），3.8（m，1H），3.62（m，1H），3.4（m，1H），2.7（m，1H），2.6（m，1H），2.5（m，1H），2.3（m，1H），2.1-1.0（m，8H）。
Example 59
3-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-1-dimethylamino-1-propylene-3-ketone
Get 1-(3-(dicyclo (2.2.1) heptan-2-base is amino)-4-p-methoxy-phenyl) ketene (1.5 grams, 5.84 mmoles) is dissolved in 5 milliliters of three-dimethylamino methylmethanes, refluxed 30 minutes.The reaction mixture water is suppressed product ethyl acetate extraction 3 times.With the organic layer water that merges, salt solution washs, and filters and make 1.4 in vacuum concentration to restrain (77.3%) enamine-ketone products.
1H NMR（60MHz，CDCl 3）：delta7.7（d，1H，12Hz），7.5-7.2（m，2H），7.0-6.7（m，1H），5.65（d，1H，12Hz），4.8-4.1（m，1H），3.95（bs，3H），3.0（s，6H），2.9-1.0（m，10H）。
Use similar approach, prepare from suitable reactant: 3-((3-1,2-indanyl-2-base oxygen)-4-p-methoxy-phenyl]-1-dimethylamino-1-propylene-3-ketone.Yield 71.8%.
1H NMR（60MHz，CDCl 3）：delta7.8-6.6（m，8H），6.7（d，1H，J＝12Hz），3.8（s，3H），3.3（m，4H），2.8（bs，6H）。
Example 60
4-(3-(dicyclo (2.2.1) heptan-2-base is amino)-4-p-methoxy-phenyl)-and 4-hydroxyl-1,2,3,4-tetrahydrochysene-2-pyrimidone
Enamine-ketone (0.9 gram, 2.9 mmoles) and the urea (0.21 gram, 3.5 mmoles) of getting example 59 are dissolved in 10 milliliters of ethanol, handle and reflux 1 hour with 4 milliliters of 1N HCl, will react cooling, water inhibition, product ethyl acetate extraction 2 times.With the organic layer that merges, with the salt solution washing, drying is filtered and vacuum concentration.Crude product with CHCl/ hexane recrystallization, is made 0.55 gram (57.5%) crystallized product, and product is 7: 3 inside/outside mixtures of isomer.
Fusing point: 167-169 ℃ (decomposition)
1H NMR（300MHz，CDCl 3）：delta7.7-7.4（m，3H），6.8（m，1H），6.18（m，1H），5.5（b，2H），4.7（m，.7H），4.3（m，.3H），3.95（s，3H），2.8-1.2（m，10H）。
C 18H 22N 2O 4Molecular weight calculated value: 330.1580
HRMS molecule measuring definite value: 330.1614
Example 61
4-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-1,2-dihydro-2-pyrimidone
Get example 60 hydroxypyrimidinone (0.2 gram, 0.61 mmole) be dissolved in 5 milliliters of ethanol, with 2.5 milliliters of 1N HCl processing and refluxed 6 hours.Reaction mixture is cooled to room temperature, and water suppresses, product ethyl acetate extraction 3 times, and the washing organic layer, drying is filtered and in vacuum concentration, the crude product crystallization from vinyl acetic monomer that obtains is folded, and making 60 milligrams of (31.5%) crystalline solids is pyrimidone.Product is 7: 3 mixtures of inside/outside bicyclic alkyl isomer.
Fusing point: 220 ℃
1H NMR（300MHz，CDCl 3）：7.8-7.45（m，3H），6.9（m，1H），6.8（m，1H），5.15（m，1H），4.75（m，.7H），4.35（m，.3H），3.95（bs，3H），2.8-1.2（m，10H）。
C 18H 20N 2O 3Molecular weight calculated value: 312.1474
HRMS molecule measuring definite value: 312.1520
Example 62
5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) imidazoles (1,2-a) pyrimidine
Get real 59 enamine-ketone (0.4 gram, 1.27 mmoles) and 2-aminooimidazole sulfonate, be dissolved in 5 milliliters of ethanol, with 0.5 milliliter of Shen salt acid treatment and refluxed 1.5 hours.Reaction mixture cooling and water are suppressed, with pH regulator to 9, product ethyl acetate extraction 2 times.The organic layer that merges washes with water, and drying in vacuum concentration, folds crude product crystallization from ether, makes 0.11 gram (28.9%) crystalline solid product.Product contains 7: 3 inside/outside mixtures of isomer.
Fusing point: 140-141 ℃
1H NMR（300MHz，CDCl 3）：delta8.6（d，1H），7.81（bs，1H），7.74（bs，1H），7.3-7.0（m，3H），6.8（m，1H），4.63（m，.7H），4.21（m，.3H），3.95（bs，3H），2.7-1.1（m，10H）。
C 20H 21N 2O 3Molecular weight calculated value: 353.1634
HRMS molecule measuring definite value: 335.1631
Example 63
7-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) pyrazoles (2,3-a) pyrimidine
Enamine ketone (0.40 gram, 1.27 mmoles) and the 3-amino-pyrazol (0.16 gram, 1.9 millimoles) of getting example 59 are dissolved in the ethanol, with 0.5 milliliter of dense HCl processing and refluxed 1 hour.Reaction mixture cooling and water are suppressed, and pH regulator to 9, product be with ethyl acetate extraction 2 times, the organic layer that washing merges, drying is filtered, in the vacuum concentration crude product through 150 order SiO 2Chromatography is made elutriant with the ester acetoacetic ester.Be dissolved in free alkali in the ether and drip concentrated hydrochloric acid and handle, filter and collect hydrochloride, obtain 0.15 gram (35.6%) yellow crystal solid, this product is 7: 3 inside/outside isomers.
Fusing point: 148-149 ℃
1H NMR（300MHz，CDCl 3）：delta8.5（m，1H），8.16（m，1H），7.7-7.6（m，2H），7.1-7.0（d，1H，J＝6Hz），6.9（m，1H），6.75（m，1H），4.7（m，.7H），4.35（m，.3H），3.85（bs，3H），2.7-1.1（m，10H）。
C 20H 21N 3O 2Molecular weight calculated value: 335.1633
HRMS molecule measuring definite value: 335.1659
Example 64
5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-1,2,3,4-tetrahydrochysene-2-pyrimidone
Get α-methylene amino that example 46 obtains-((dicyclo (2.2.1) heptan-2-base oxygen base)-4-p-methoxy-phenyl in the 3-() acetaldehyde (0.60 gram, 2.08 mmole) and urea (0.20 the gram, 3.3 mmole) be dissolved in 10 milliliters of ethanol, with 2 milliliters of dense HCl solution-treated and refluxed 1.5 hours.With the reaction mixture cooling, use NH 4The neutralization of OH solution extracts product 4 times with vinyl acetic monomer, with organic layer washing, drying, in vacuum concentration.The resistates crystallization from ether that obtains is separated out, obtains 0.38 gram (58.6%) 5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-1,2-dihydro-2-pyrimidone, product is identical with example 47 descriptions.
Pyrimidone (0.38 gram, 1.22 mmoles) is dissolved in 20 milliliters of ethanol, with 0.5 gram Raney's nickel, 40 pounds/inch 2Hydrotreatment, and refluxed 18 hours.To react cooling, through diatomite filtration, filtrate is in vacuum concentration.With resistates vinyl acetic monomer recrystallization, making 0.12 gram (31.8%) crystalline solid is dihydropyrimidinonesand, and product contains 7: 3 mixtures of inside/outside norborneol isomer.
1H NMR（300MHz，CDCl 3）：delta7.1（bs，1H），6.9-6.7（m，3H），6.4（d，1H，J＝5Hz），5.4（bs，1H），4.65（m，.7H），4.4（bs，2H），4.25（m，.3H），3.85（s，3H），2.7-1.2（m，10H）.
C 18H 22N 2O 3Molecular weight calculated value: 315.1630
HRMS(M+) molecule measuring definite value: 314.1644
Use similar approach, from 5-(outside the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-1, the outer isomer of 2-dihydro-2-pyrimidone (example 47) prepares the outer isomer of title compound, yield 60.3% through above-mentioned hydrogenization.
1H NMR（300MHz，CDCl 3+CD 3OD）：delta6.7（m，3H），6.2（bs，1H），4.15（m，1H），3.78（s，3H），3.3（bs，2H），2.4-1.0（m，10H）。
C 18H 22N 2O 3Molecular weight calculated value: 314.1625
HRMS(M+) molecule measuring definite value: 314.1647
Example 65
5-(3-(dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) six hydrogen-2-pyrimidone
The tetrahydro pyrimidine ketone (0.30 gram, 0.882 mmole) of getting example 64 is dissolved in 15 ml methanol, handles with 0.3 gram Raney's nickel, in 40 pounds/inch 2Hydrogenation 6 hours.With reaction mixture through diatomite filtration, through MgSO 4Drying is filtered, and in vacuum concentration, with the ether development, obtains 0.275 gram (98%) crystalline solid and is the ring urea.Product is 7: 3 mixtures of inside/outside bicyclic alkyl isomer.
Fusing point:＞220 ℃
1H NMR（300MHz，CDCl 3）：delta6.85-6.6（m，3H），5.1（bs，2H），4.65（m，.7H），4.25（m，3H），3.9（bs，3H），3.5（m，4H），3.1（m，1H），2.7-1.1（m，10H）.
Molecular weight calculated value 316.1787
MS(M+) molecule measuring definite value: 316
Use above-mentioned method of operating, prepare from suitable reactant:
5-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl) six hydrogen-2-pyrimidone, yield 75.6%
Fusing point: 212-214 ℃.
1H NMR（300MHz，DMSO）：delta7.2-6.8（m，7H），6.3（bs，2H），5.2（m，1H），3.7（s，3H），3.4-3.2（m，7H），3.0（m，2H）.
13C NMR（75.43MHz，DMSO）：delta156.0，148.4，146.8，140.8，132.9，126.4，124.6，119.5，113.9，112.2，79.2，77.9，55.4，45.5，36.9。
C 20H 22N 2O 3Molecular weight calculated value: 338.1636
HRMS(M+) molecule measuring definite value: 338.1629
5-(in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl) six hydrogen-2-pyrimidone, yield 66.5%
1H NMR（300MHz，CDCl 3）：7.2（bs，2H），6.8-6.7（m，3H），4.6（m，1H），3.8（s，3H），3.4（m，4H），3.15（m，1H），2.6-1.0（m，10H）。
5-(3-(is outer-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl) six hydrogen-2-pyrimidone, yield 82%
1H NMR（300MHz，CDCl 3）：delta6.8-6.7（m，3H），5.4（bs，2H），4.15（m，1H），3.8（s，3H），3.4（m，4H），3.15（m，1H），2.4-1.0（m，10H）。
C 18H 24N 2O 3Molecular weight calculated value: 316.1757
HRMS(M+) molecule measuring definite value: 316.1801
Example 66
4-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl)-and 4-hydroxyl-1,2,3,4-tetrahydrochysene-2-pyrimidone and 4-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl)-1,2-dihydro-2-pyrimidone
Get that example 59 obtains 2, enamine-ketone that 3-indanyl substituted indenyl replaces (1.5 grams, 4.45 mmoles) and urea (0.4 restrains 6.68 mmoles) are dissolved in 10 milliliters of ethanol and 5 milliliters of 1N HCl, reflux 2 hours.With the reaction mixture cooling, water suppresses, and uses saturated NaHCO 3The solution neutralization.Product ethyl acetate extraction 3 times, the organic layer of merging washs with salt solution, through MgSO 4Drying is filtered, and obtains the crude mixture of two kinds of products in vacuum concentration, through SiO 2Chromatography separates, and makes elutriant with vinyl acetic monomer/hexane, obtains 0.15 gram (9%) crystalline material.
4-hydroxyl-1,2,3,4-tetrahydro pyrimidine ketone product, fusing point 207-208 ℃
1H NMR（300MHz，CDCl 3/CD 3OD）：delta7.7-7.5（m，3H），7.25-7.1（m，4H），6.91（d，1H，J＝6Hz），5.3（m，1H），3.9（s，3H），3.45（dd，2H，J＝5Hz），3.3（dd，2H，J＝12Hz，J＝3Hz）。
C 20H 20N 2O 4Molecular weight calculated value: 352.1423
HRMS molecule measuring definite value: 352.1454
1,2-dihydropyrimidinonesand product
Fusing point=＞220 ℃
1H NMR（300MHz，DMSO）：delta8.1（m，1H），7.85（m，2H），7.4-7.0（m，6H），5.5（m，1H），3.95（s，3H），3.5（m，3H），3.25（bd，2H，J＝12Hz）。
C 20H 18N 2O 3Molecular weight calculated value: 334.1318
HRMS molecule measuring definite value: 334.1332
Example 67
4-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl)-1,2-dihydro-2-pyrimidone
Take from that example 59 obtains 2, enamine-ketone (800 milligrams, 2.4 mmoles) and urea (210 milligrams, 3.56 mmoles) that the 3-indanyl replaces are dissolved in 5 milliliters of 1N HCl and 15 milliliters of ethanol, reflux 4 hours.With the reaction mixture cooling, water suppresses, product ethyl acetate extraction 3 times, and organic layer is through washing, and drying also concentrates, and crude product gets 0.32 from the vinyl acetic monomer crystallization and restrains (40%) cream-coloured crystalline solid.
That describes in product that obtains and the example 66 is identical.
Example 68
4-(3-(2,3-indane-2-base oxygen)-4-p-methoxy-phenyl)-six hydrogen-2-pyrimidone
The pyrimidone (0.32 gram, 0.96 mmole) of getting example 67 is dissolved in 15 ml methanol, with Raney's nickel handle and under room temperature and 40 pounds of/inch pressure hydrogenation 8 hours, through diatomite filtration, crystallization is washed for several times with methyl alcohol with mixture.Organic layer grinds rough resistates in vacuum concentration with ether, obtain the product of 20 milligrams of (58%) crystalline solids.
Fusing point: 182-183 ℃
1H NMR（300MHz，CDCl 3）：delta7.4-6.8（m，7H），5.55（bs，1H），5.25（m，1H），5.2（bs，1H），4.6（m，1H），3.9（s，3H），3.6-3.2（m，6H），2.2（m，1H），2.0（m，1H）。
C 20H 22N 2O 3Molecular weight calculated value: 338.1631
HRNS molecule measuring definite value: 338.1665
Example 69
5-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl)-1,2,3,4-tetrahydrochysene-2-pyrimidone
5-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl)-1,2-dihydro-pyrimidone (740 milligrams, 2.2 mmoles) is dissolved in 10 milliliters of acetate, cools off in ice bath, uses NaCNBH 3(140 milligrams, 2.2 mmoles) are handled.Reaction mixture was stirred 2 hours, and then dilute with water is used ethyl acetate extraction, the organic layer of collecting is washed with water, through Na 2SO 4Drying is filtered, and in vacuum concentration, makes the title product of 640 milligrams of (87.4%) white crystalline solid.
Fusing point: 198-201 ℃
1H NMR（300MHz，CDCl 3）：delta7.5（bs，1H），7.2（m，4H），6.85（m，3H），6.38（bd，1H），5.9（bs，1H），4.3（bs，2H），3.8（s，3H），3.4-3.1（m，4H）.
Similarly, from corresponding 1, the 2-dihydropyrimidinonesand prepares 5-(in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)-1,2,3,4-tetrahydrochysene-2-pyrimidone, yield 12.4%.
Fusing point: 205-208 ℃
1H NMR（300MHz，DMSO）：delta8.2（bs，1H），6.9-6.5（m，5H），4.6（m，1H），4.2（bs，2H），3.8（s，3H），2.5-1.0（m，10H）.
Example 70
5-(3-(is outer-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl) six hydrogen-2-pyrimidone
(A) 3-((3-dicyclo (2.2.1) heptan-2-base is amino)-4-p-methoxy-phenyl) trimethylene cyanide
Get cyanoacetic acid (18.1 grams, 0.213 mmole) and outer-norborneol isovanillin ether (17.5 grams, 71.1 mmoles)) be dissolved in 80 milliliters of pyridines and 2 milliliters of piperidines, in 100 ℃ of heating 4 hours.With the reaction mixture cool to room temperature, then in impouring 200 ml waters, with 2 * 100 milliliters of ethyl acetate extractions.With the organic layer water that merges, 1N HCl, saturated NaHCO 3Solution, water washing is through MgSO 4Drying is filtered in vacuum concentration, gets brown crystalline residue, and it is used the ether recrystallization, makes the dicyanide crystalline solid of 15.1 grams (68.5%).
Fusing point: 122-123 ℃
1H（300MHz，CDCl 3）：6.82-6.65（m，3H），4.14（m，1H），3.8（s，3H），3.3（m，1H），2.77（m，1H），2.45（m，1H），2.3（m，1H），1.8-1.0（m，8H）。
(B) 3-((3-dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl) glutaramide
The trimethylene cyanide of getting from above-mentioned (A) preparation (14.8 grams, 47.7 mmoles) is dissolved in 200 milliliters of acetone, uses 100 ml waters at 0 ℃, 33.8 milliliters of 30%H 2O 2With 21.2 milliliters of 10%Na 2CO 3Handle.Sluggish heated up and stirring at room 14 hours.Reaction mixture is concentrated into 150 milliliters, resistates is distributed between 100 ml waters and 200 milliliters of vinyl acetic monomers.Wash organic layer with water, through MgSO 4Drying is filtered, and in vacuum concentration, gets rough diamide, and it is developed with ether, and obtaining 13.8 gram (84%) crystalline solids is diamide.
Fusing point: 175-177 ℃
1H NMR（300MHz，CDCl 3）：6.8-6.6（m，3H），4.15（m，1H），3.75（s，3H），3.6（m，1H），2.6-1.0（m，14H）。
(C) six hydrogen-2-pyrimidone 5-(3-(is outer-dicyclo (2.2.1) heptan-2-base oxygen)-4-p-methoxy-phenyl)
Get glutaramide (B) (1 gram, 2.89 mmoles) and be dissolved in pyridine.In this solution, add lead tetra-acetate (2.72 gram, 6.13 mmoles), with mixture in stirring at room 20 hours.The reaction mixture dilute with water is with 2 * 100 milliliters of ethyl acetate extractions.Organic layer washs with salt solution, through MgSO 4Drying is filtered, in vacuum concentration.Crude product is separated out from the vinyl acetic monomer crystallization, get the ring urea crystalline solid of 0.6 gram (65.7%).
Fusing point: 191-192 ℃
1H NMR（300MHz，CDCl 3）：6.8-6.6（m，3H），5.35（bs，2H），4.15（m，1H），3.8（s，3H），3.4（m，4H），3.1（m，1H），2.5-1.0（m，10H）。
Preparation A
3-(outer-dicyclo (2.2.1) heptan-2-base oxygen)-4-methoxybenzaldehyde
In-dicyclo (2.2.1) heptan-2-alcohol (5.6 grams, 5.0 mmole), isovanillin (7.6 grams, 50.0 mmole) and triphenylphosphine (19.65 the gram, 75.0 mmole) be dissolved in 250 milliliters of anhydrous tetrahydro furans, in this mixture, drip diethylazodicarboxylate's (11.80 milliliters, 75.0 mmoles), reaction mixture reflux and continuation were refluxed 48 hours.Then reaction mixture is cooled to room temperature, with 500 milliliters of ether dilutions.The organic layer of collecting is with 2 * 200 ml waters, 2 * 200 milliliters of 0.5N sodium hydroxide solutions, and 1 * 100 ml water and 1 * 100 milliliter of saturated nacl aqueous solution wash.Organic layer filters, in vacuum concentration through anhydrous sodium sulfate drying.With reaction mixture through the SiO(32-60 order), make elutriant with vinyl acetic monomer/hexane.Collect suitable part, concentrate the just glassy yellow oily matter of outer-compound that makes 5.35 grams (43.5%).
1H NMR（300MHz，CDCl 3）：delta9.83（s，1H），7.4（dd，1H，J＝9Hz，J＝1Hz），7.3（d，1H，J＝1Hz），6.95（d，1H，J＝9Hz），4.28（m，1H），3.91（s，3H），2.6-1.0（m，10H）。
Similarly, outer-three ring (3.2.1.0 of 3-( 2,6) last of the ten Heavenly stems-4-base oxygen)-the 4-methoxybenzaldehyde, can be from three ring (3.2.1.0 2,6) decyl alcohol-4 makes yield 68.3%.
1H NMR（300MHz，CDCl 3）：delta9.8（m，1H），7.4（m，2H），6.95（m，1H），4.95（m，1H），4.0（s，3H），2.8-1.2（m，14H）。
-three ring (3.2.1.0 in the 3-( 2,6) last of the ten Heavenly stems-8-base oxygen)-the 4-methoxybenzaldehyde, can make yield 60.2% from three ring (3.2.1.0) decyl alcohol-8.
1H NMR（300MHz，CDCl 3）：delta9.8（s，1H），7.4-7.3（m，2H），6.85（m，1H），4.8（m，1H），3.85（s，3H），2.3-.9（m，14H）。
Preparation B
2-(dicyclo (2.2.1) heptan-2-yl)-1,3 benzo dioxole
The pyrocatechol (22.7 grams, 206 mmoles) of getting Norcamphor (25 grams, 227 mmoles) is dissolved in 500 milliliters of toluene, reflux in the presence of the two-toluenesulphonic acids of catalytic amount.Reaction mixture flows through (15 hours night last time at the Soxhlet's extractor that the 3A molecular sieve is housed.Reaction mixture is cooled to room temperature, removes toluene in vacuum.Resistates is dissolved in 500 milliliters of ether, and the ether layer is with 1 * 100 milliliter of 2N NaOH solution and 2 * 100 ml waters, 1 * 100 milliliter of saturated NaCl solution washing, organic layer is through the MgSO drying, filter, in vacuum concentration, making 35.2 gram (85%) white solids is a little tea phenol ketals.
Fusing point: 42-43 ℃
1H NMR（300MHz，CDCl 3）：delta6.8（m，4H），2.5-1.2（m，10H）.
Press aforesaid operations, with three ring (3.2.1.0 2,6)-decanone-8 is converted into 2-(three ring (3.2.1.0 2,6) last of the ten Heavenly stems-the 8-yl)-1,3-benzo dioxole.Yield 84.8%.
1H NMR（300MHz，CDCl 3）：delta6.9（m，4H），2.7-1.0（m，14H）;
Benzo dicyclo (2.2.1) heptanone-2 is converted into 2-(benzo dicyclo (2.2.1) heptan-2-yl)-1,3-benzo dioxole, yield 93.5%.
1H NMR（300MHz，CDCl 3）：delta7.4-7.2（m，4H），6.9-6.7（m，4H），3.6（m，2H），2.6（m，1H），2.4（m，1H），2.25（m，1H），2.05（m，1H）。
Preparation C
In the 2-(-and dicyclo (2.2.1) heptan-2-base oxygen) phenol
Get aluminum chloride (4.9 grams, 37 mmoles) and be suspended in 50 milliliters of dry ethers, be cooled to 0 ℃.The lithium aluminum hydride ethereal solution (12.5 mmole) that in this solution, adds 12.5 milliliters of 1M.This slurry is stirred half an hour, and add 2-(dicyclo (2.2.1) heptan-2-base oxygen)-1,50 milliliters of diethyl ether solutions of 3-benzo dioxole (5.00 grams, 25 mmoles), with this solution stirring half an hour, drip the Seignette salt saturated solution then carefully and come inhibited reaction.With the slurry that obtains with 2N NaoH solution alkalize to pH be 12, and then with 10% hydrochloric acid soln residual titration to pH7, water layer and organic layer are separated, and water layer washs with 2 * 200 ml waters and 1 * 200 milliliter of saturated nacl aqueous solution with 2 * 150 milliliters of ether re-extracts, the organic layer of merging.The ether layer filters through dried over mgso, and in vacuum concentration, making 4.6 gram (90%) transparent oil is phenol.
1H NMR（300MHz，CDCl 3）：delta7.0-6.7（m，4H），6.7（bs，1H），4.7（m，1H），2.68（m，1H），2.36（m，1H），2.14（m，1H），1.96（m，1H），1.66（m，1H），1.46（m，4H），1.22（m，1H）。
-three ring (3.2.1.0 in the 2-( 2,6) last of the ten Heavenly stems-8-base oxygen) phenol is from 2-(three ring (3.2.1.0 2,6) last of the ten Heavenly stems-the 8-yl)-1, the preparation of 3-benzo dioxole, yield 97%.
1H NMR（300MHz，CDCl 3）：delta7.0-6.7（m，4H），5.7（s，1H），4.65（m，1H），2.6-1.0（m，14H）。
In the 2-(-benzo dicyclo (2.2.1) heptan-2-base oxygen) phenol from 2-(benzo two (2.2.1)-heptan-the 2-yl)-1,3-benzo dioxole, preparation, yield 92.6%.
Preparation D
In the 4-bromo-2-(-and dicyclo (2.2.1) heptan-2-base oxygen) phenol
In the 2-(-and dicyclo (2.2.1) heptan-2-base oxygen) (3.93 grams, 19.3 mmoles) be dissolved in 200 liters of chloroforms and be cooled to-20 ℃.In this solution in half an hour 1 mole of chloroformic solution of dripping bromine (3.09 gram, 19.3 mmoles), after dropwising solution is risen to room temperature, in vacuum concentration, make 5.6 gram (～100%) list-bromine compoundss.
1H NMR（300MHz，CDCl 3）：delta7.0-6.7（m，3H），5.65（bs，1H），4.55（m，1H），2.6（m，1H），2.3（m，1H），2.1（m，1H），1.85（m，1H），1.6（m，1H），1.4（m，4H），1.15（m，1H）。
Use similar approach, with-three ring (3.2.1.0 in the 2-( 2,6) last of the ten Heavenly stems-8-base oxygen) phenol conversion is corresponding 4-bromo derivative, yield 99%.
1H NMR（300MHz，CDCl 3）：delta7.0-6.7（m，3H），5.75（s，1H），4.65（m，1H），2.7-1.0（m，14H）.
In the 2-(-and benzo dicyclo (2.2.1) heptan-2-base oxygen) phenol conversion is corresponding 4-bromophenol, it is quantitative that yield is essentially.
1H NMR（300MHz，CDCl 3）：delta7.25-6.7（m，7H），3.65（m，1H），3.48（m，1H），2.5-1.8（m，6H）.
Preparation E
In 4-bromo-2-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-anisole
Interior-bromophenol (5.60 gram, 19.9 mmoles) of getting preparation D is dissolved in 50 milliliters of anhydrous dimethyl formamides, with indole methyl hydride (3.55 grams, 25 mmoles) and Anhydrous potassium carbonate (3.46 grams, 25 mmoles) processing, in stirring at room 15 hours.This solution is injected 600 milliliters of 0.7N NaoH solution.Water layer extracts with 2 * 300 milliliter of one ether, and the organic layer of merging is with 4 * 100 ml waters and 1 * 100 milliliter of saturated nacl aqueous solution washing.Organic layer filters through dried over mgso, in vacuum concentration, makes 5.14 gram (87%) methyl ethers.
1H NMR（300MHz，CDCl 3）：delta6.9-6.6（m，3H），4.55（m，1H），3.82（s，3H），2.6（m，1H），2.3（m，1H），2.05（m，2H），1.6（m，1H），1.42（m，4H），1.16（m，1H）.
Use similar approach, prepare following compounds from suitable brominated phenol:
-three rings (3,2,1,0 in 4-bromo-2-( 2,6) the basic oxygen in the last of the ten Heavenly stems-8)-the 4-anisole:
1H NMR（300MHz，CDCl 3）：delta6.9（m，2H），6.6（m，1H），4.5（m，1H），3.8（s，3H），2.7-1.0（m，14H）.
In 4-bromo-2-(-benzo two (2.2.1) heptan-2-base oxygen-4-anisole:
1H NMR（300MHz，CDCl 3）：delta7.2-6.9（m，6H），6.6（m，1H），5.0（m，1H），3.65（m，1H），3.50（s，3H），3.35（m，1H），2.4（m，1H），1.85（m，1H），1.75（m，1H），1.2（m，1H）.
Preparation F
Dicyclo (2.2.2) suffering-2-alcohol
Dicyclo (2.2.2)-2-octane (20 grams, 185 mmoles) is dissolved in 100 milliliters of anhydrous tetrahydro furans and is cooled to 0 ℃.In this solution, drip 1 mole of tetrahydrofuran solution of borane-tetrahydrofuran (THF) mixture (200 mmole).Stirred 1 hour, reaction mixture slowly rises to room temperature.With 50 milliliters of 2N NaoH solution and 100 milliliters of 30%H 2O 2Come inhibited reaction at leisure, be warming up to then 50 ℃ 1 hour.Solution dilutes with 500 milliliters of ether.Water layer is saturated and extract with 100 milliliters of ethers with NaCl.1 * 100 milliliter of sodium bisulfite saturated solution of organic layer, 1 * 100 ml water and 1 * 100 milliliter of salt solution washing, ether layer anhydrous sodium sulfate drying filters, and in vacuum concentration, making 19.27 gram (83%) white solids is the dicyclo octanol.
Fusing point: 210-212 ℃
1H NMR（90MH 2，CDCl 3）：delta3.93（m，1H），2.5（bs，1H），2.3-1.0（m，12H）.
Preparation G
In-three the ring (3.2.1.0) last of the ten Heavenly stems-2-alcohol
Getting three cyclooctanones (9.57 grams, 63.8 mmoles) is dissolved in 350 milliliters of anhydrous tetrahydro furans and is cooled to 0 ℃.Reaction mixture is handled with the toluene solution (48 milliliters 1.5 moles, 7 mmoles) of diisobutylaluminium hydride.The slow property of reaction mixture is risen to room temperature, and at room temperature stirred 14 hours.Also suppress with 500 milliliters of ether diluted reaction mixtures then with 20 milliliters of Seignette salt saturated solutions.Water layer and organic layer layering are opened, and water layer is with 100 milliliters of ether re-extracts.The organic layer of merging washs with the phosphate buffered saline buffer of 1 * 100 milliliter of pH7,1 * 100 milliliter of salt solution, through dried over mgso, filters, and in vacuum concentration, makes (95.8%) clear, viscous oil of the just interior compound of 9.3 grams.
1H NMR（300MHz，CDCl 3）：delta4.15（m，1H），2.45（m，1H），2.2-1.7（m，13H）。
Preparation H
-three ring (3.2.1.0 in the 3-( 2,6) last of the ten Heavenly stems-8-base oxygen (4-methoxybenzaldehyde
Get the three ring decyl alcohol (5.17 grams, 34.0 mmoles) that preparation G obtains, isovanillin (5.17 grams, 34.0 mmole), triphenylphosphine (10.7 grams, 40.8 mmoles) and azo-carboxylic acid's diethyl ester (6.4 milliliters, 40.8 mmoles) are dissolved in 200 milliliters of tetrahydrofuran (THF)s and refluxed together 36 hours.Reaction mixture is cooled to room temperature, with 400 milliliters of ethers and the dilution of 100 ml waters.Water layer and organic layer are separated, use MgSO 4Drying is filtered, and in vacuum concentration, product is through flash chromatography chromatography (SiO 2, 10% vinyl acetic monomer/hexane).Collect suitable part, give vacuum concentration, make 1.28 grams (14%) three ring, two aromatic aldehydes.
1H NMR（300MHz，CDCl 3）：delta9.8（s，1H），7.43（dd，1H，J＝9Hz，J＝1Hz），7.3（d，1H，J＝1Hz），6.9（d，1H，J＝9Hz），4.3（m，1H），3.9（s，3H），2.4-.9（m，14H）。
Preparation I
In the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-methoxybenzoic acid
In 3-(-two (2.2.1) heptan-2-base oxygen)-add Jones reagent (6.5 milliliters of 2.5M solution, 16.9 mmoles) in 50 milliliters of acetone solns of 4-methoxybenzaldehyde (2.46 grams, 10 mmoles).With reaction mixture in stirring at room 2 hours.Reaction mixture dilutes with 100 ml waters, with 2 * 50 milliliters of ethyl acetate extractions.With the organic layer salt solution that merges, water washing through dried over mgso, is filtered, and in vacuum concentration, obtains crude acid, it is folded from the ether crystallization make 1.9 gram (72.5%) yellow crystals for sour.
Fusing point: 170-171 ℃
Preparation J
(in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-methoxyl methyl benzoate
Get in the 3-(of preparation I-(2.2.1 (heptan-2-base oxygen)-4-methoxybenzoic acid (1.9 grams, 7.25 mmoles) is dissolved in methyl alcohol to dicyclo, handles with the vitriol oil (1.1 milliliters, 10 mmoles), refluxes 3 hours.Reaction mixture is cooled to room temperature, in vacuum concentration to 15 milliliter, with 50 milliliters of vinyl acetic monomers dilutions, water, NaHCO 3The aqueous solution, water washing through dried over mgso, is filtered, and in vacuum concentration, making 1.9 gram (94.9%) thickness yellow oils is ester.
1H NMR（60MHz，CDCl 3）：delta10.0（bs，1H），7.6-7.3（m，2H），6.8-6.6（m，1H），4.6（m，1H），3.8（s，3H），2.7-1.0（m，10H）。
Preparation K
The 2-(methylsulfonyl)-1-(in the 3-(-dicyclo (2.2.1)-heptan-2-base oxygen)-the 4-p-methoxy-phenyl) ketene
The sodium hydride (50% in oil, 72 grams, 15 mmoles) of getting the pentane elution is suspended in 10 milliliters of anhydrous dimethyl sulfoxides, is heated to 70 ℃ and keeps 45 minutes.Reaction mixture is cooled to room temperature also with 10 milliliters of tetrahydrofuran (THF)s dilutions.Reaction mixture is cooled to 0 ℃ again, the introversive tetrahydrofuran solution that wherein drips the ester (1.9 grams, 6.9 mmoles) of preparation J in 20 minutes.Reaction mixture was stirred 1.5 hours at 5 ℃, again stirring at room 1.5 hours.In 30 milliliters of ice/water of reaction mixture impouring, with 1N HCl acidifying, product is with 3 * 30 milliliters of dichloromethane extractions.The organic layer that merges is through MgSO 4Drying is filtered, and in vacuum concentration, making 1.5 gram (yield 67.5%) yellow viscous oils is sulfoxide.
1H NMR（60MHz，CDCl 3）：delta7.6-7.2（m，2H），7.0-6.7（m，1H），4.6（m，1H），4.35（d，J＝6Hz），3.9（s，3H），2.75（s，3H），2.7-1.0（m，10H）.
Preparation L
2-hydroxyl-2-(sulphomethyl)-1-(in the 3-(-dicyclo (2.2.1) heptan-2-base oxygen)-the 4-p-methoxy-phenyl) ketene
The sulfoxide (1.5 grams, 4.66 mmoles) of getting preparation K is dissolved in 15 milliliters of vinyl acetic monomers, handles with 1N HCl15 milliliter.Reaction is warming up to 50 ℃ to be kept 16 hours.The refrigerative reaction mixture suppressed with 50 ml waters and with 2 * 50 milliliters of ethyl acetate extractions.The organic layer that merges washes with water 4 times, through dried over mgso, filters, and in vacuum concentration, making 1.48 gram (98.6%) toughening oil is hydroxyl sulfide.
1H NMR（60MHz，CDCl 3）：delta7.7-7.4（m，2H），6.9-6.7（m，1H），4.6（m，1H），3.9（s，3H），2.7-1.0（m，10H），2.1（s，3H）.
Preparation M
3-(dicyclo (2.2.1)-heptan-2-base oxygen)-4-p-methoxy-phenyl oxalic dialdehyde
The hydroxyl sulfide (1.48 grams, 4.6 mmoles) of getting preparation L is dissolved in 10 milliliters of chloroforms, uses Cu(oAc) 2H 2O handles.Reaction mixture was stirred 1.5 hours, and cooling is through diatomite filtration.Diatomite filter is washed 3 times with chloroform.Add 20 ml waters in the organic layer of collecting, mixture alkalizes with solid sodium carbonate, and organic layer is separated, and washes with water, through dried over mgso, filters, and in vacuum concentration, making 1.3 gram (96.8%) xanchromatic toughening oil is α-keto-aldehyde.
1H NMR（60MHz，CDCl 3）：delta7.8-7.4（m，2H），7.0-6.7（m，1H），4.8（m，2H），3.9（s，3H），2.8-1.0（m，10H）.
Preparation N
3-(1,2-indane-2-base oxygen)-the 4-methoxybenzaldehyde
Get 1-1,2-indanol 5 grams, 37 mmoles), isovanillin (7.08 grams, 46 mmoles), triphenylphosphine (12.21 grams, 46 mmoles), diethylazodicarboxylate's (8.10 grams, 46 mmoles) is dissolved in 250 milliliters of tetrahydrofuran (THF)s and is back to 1,2-indanol completely dissolve (detecting with thin-layer chromatography).With reaction mixture cooling and with the dilution of 100 ml waters, with 3 * 50 milliliters of extracted with diethyl ether, with the organic layer of collection with 2 * 50 ml waters, 2 * 50 milliliters of pH=73M phosphate buffered saline buffers and 2 * 50 milliliters of salt solution washings, organic layer filters through dried over mgso, in vacuum concentration, fast through SiO 2(4: 11: 1 hexane/ethyl acetate of 32-60 order) makes 2.29 gram (23.1%) white solids is 2,3-indanyl ether.
1H NMR（300MHz，CDCl 3）：delta9.7（s，1H），7.2（m，2H），7.0-6.9（m，4H），6.73（m，1H），5.05（m，1H），3.7（s，1H），3.25（dd，2H，J＝13Hz，J＝7Hz），3.15（dd，2H，J＝13Hz，J＝3Hz）。
Preparation O
Outside the 3-(-benzo dicyclo (2.2.1)-heptan-2-base oxygen)-the 4-methoxybenzaldehyde
(4 grams, 0.022 mole is dissolved in 50 milliliters of toluene, handles with the isovanillin (5.19 grams, 0.034 mole) and the tosic acid of catalytic amount to get benzo norborneol manthanoate.With reaction mixture refluxed 15 hours, cooling was diluted with 100 milliliters of ethers.With organic layer 1N NaoH solution, water, salt solution washing.Through dried over mgso, filter, in vacuum concentration.Crude product is through flash chromatography chromatography (SiO 210 → 50% vinyl acetic monomers/hexane), making 0.78 gram yellow oil is aldehyde.
1H NMR（300MHz，CDCl 3）：delta9.7（s，1H），7.4-6.9（m，7H），4.1（m，1H），3.9（s，3H），3.6（bs，1H），3.4（bs，1H），2.25（m，1H），1.95（m，3H）。
Preparation P
3-(is outer-dicyclo (2.2.1) heptan-2-base oxygen)-4-anisole methyl alcohol
3-(is outer-dicyclo (2.2.1)-heptan-2-base oxygen)-4-methoxybenzaldehyde (3.6 grams, 14.6 mmoles) is dissolved in 50 ml methanol, adds sodium borohydride (0.18 gram, 4.9 mmoles) in batches in this solution.Reaction mixture was stirred 45 minutes in 25 ℃.Reaction suppresses with 2 ml waters, is concentrated into 25 milliliters, and reactant is distributed between 50 milliliters of vinyl acetic monomers and 50 ml waters.Separate organic layer,,, filter,, make 3.37 gram (93.1%) viscous oils and be alcohol in vacuum concentration through dried over mgso with the salt solution washing.
1H NMR（60MHz，CDCl 3）：delta6.8（m，3H），4.6（bs，2H），4.2（m，1H），3.8（s，3H），2.8-1.0（m，10H）。
Similarly, suitable prepared in reaction following compounds:
3-(dicyclo (2.2.1)-heptan-2-base oxygen)-4-anisole methyl alcohol from 3-(dicyclo (2.2.1)-heptan-2-base oxygen)-mixture of isomers of 4-methoxybenzaldehyde prepares, yield 94.7%, product are 7: 3 inside/outside mixtures of isomer.
1H NMR（60MHz，CDCl 3）：delta6.9（m，3H），4.7（m，7H），4.6（bs，2H），4.2（m，3H），3.9（bs，3H），2.6（bs，3H），2.6-1.0（m，10H）;
3-(1,2-indane-2-base oxygen)-4-methoxy-benzyl alcohol, yield 91%.
1H NMR（300MHz，CDCl 3）：delta7.2（m，4H），7.0-6.8（m，3H），5.2（m，1H），4.6（s，1H），3.8（s，3H），3.4（m，1H），3.3（m，2H）;
In the 3-(-dicyclo (2.2.1)-heptan-2-base oxygen)-4-methoxy-benzyl alcohol yield 98%.
1H NMR（300MHz，CDCl 3）：delta6.8（m，3H），4.5（m，1H），4.45（bs，1H），3.75（s，3H），2.8（m，1H），2.6（m，1H），2.2-1.0（m，8H）。
Preparation Q
Outside the 3-(-dicyclo (2.2.1)-heptan-2-base oxygen)-4-methoxy-benzyl bromine
Alcohol (3.3 grams, 13.3 mmoles) and the carbon tetrabromide (8.83 grams, 26.6 mmoles) of getting preparation P are dissolved in 50 milliliters of ethers, handle (5.23 grams, 19.95 mmoles) with triphenylphosphine.Reaction mixture in stirring at room 2 hours, is removed by filter triphenyl phosphine oxide, and filtrate is in vacuum concentration.Resistates is developed with vinyl acetic monomer.The solid that obtains is further used the flash chromatography chromatography purification, make elutriant with 75% hexane/ethyl acetate.Collect suitable part and in vacuum concentration, obtain thick yellow oil 3.05 grams (73.7%) and be bromide.
1H NMR（60MHz，CDCl 3）：delta6.8（m，3H），5.4（bs，2H），4.2（m，1H），3.8（s，3H）），2.6-1.0（m，10H）.
Make 3-(dicyclo (2.2.1) heptan-2-base oxygen with similar approach from corresponding alcohol)-the inside/outside isomer of 4-p-methoxy-phenyl bromide be about 7: 3 mixture
1H NMR（60MHz，CDCl 3）：delta6.8（m，3H），4.7（m，7H），4.6（bs，2H），4.2（m，3H），3.85（bs，3H），2.6-1.0（m，10H）。
Preparation R
Outside the 3-(-dicyclo (2.2.1)-heptan-2-base oxygen)-4-p-methoxy-phenyl prussiate
Getting sodium cyanide (80 milligrams, 16.4 mmoles) is suspended among 30 milliliters of DMSO and is warming up to 70 ℃.The solution of bromide (3 grams, 9.65 mmoles) in 5 milliliters of DMSO that in this NaCN/DMSO suspension, adds preparation Q.Reaction mixture was stirred 1 hour under this temperature.With the reaction mixture cooling, suppress with 50 ml waters, with 3 * 50 milliliters of ether extractions.Wash the organic layer that merges with water 3 times through dried over mgso, filter, in vacuum concentration, obtain brown resistates, it through the SiO chromatography, is made elutriant with 75% hexane/ethyl acetate, suitable part at vacuum concentration, is made heavy-gravity yellow oil 1.2 grams (48%) and is nitrile.
1H NMR（60MHz，CDCl 3）：delta6.9（m，3H），4.25（m，1H），3.85（s，2H），3.7（s，2H），2.65-1.0（m，10H）。
Use similar approach, with precursor benzyl bromide prepare 3-(dicyclo (2.2.1)-heptan-2-base oxygen)-4-methoxy-benzyl prussiate be about 7: 3 inside/outside isomer mixture.
1H NMR（300MHz，CDCl 3）：delta6.9-6.7（m，3H），4.65（m，7H），4.25（m，3H），3.85（bs，3H），3.7（bs，2H），2.65-1.1（m，10H）.
Preparation S
Outer-three ring (3.3.1.1 of 3-( 3,7) last of the ten Heavenly stems-2-base oxygen)-4-anisole benzaldehyde
Get isovanillin (10.75 grams, 70.72 mmoles), 2-adamantanol (8.6 grams, 56.5 mmole), triphenyl phosphine (18.53 gram, 70.72 mmoles) and diethylazodicarboxylate's (11.12 milliliters, 70.72 mmoles) were dissolved in 280 milliliters of tetrahydrofuran (THF)s and reflux 24 hours.With the reaction mixture cooling, with 500 milliliters of ether dilutions, with 2 * 100 ml waters, 2 * 100 milliliters of 0.5N NaoH solution, 2 * 100 ml waters, the agent of 1 * 100 milliliter of 3MPh7 phosphoric acid hydrochloric acid, 1 * 100 milliliter of salt solution washing.Organic layer in vacuum concentration to 100 milliliter, with 500 milliliters of hexanes dilutions, is settled out triphenyl phosphine oxide.Solution is through MgSO 4Drying is filtered, in vacuum concentration.Separate this pure aldehyde with the bisulfite salt formation/release steps of standard, make 5.29 gram (33%) viscosity buttery aldehyde.
1H NMR（300MHz，CDCl 3）：delta7.4（m，2H），6.95（m，1H），4.52（bs，1H），3.92（s，3H），2.3-1.4（m，14H）。
Preparation T
Outer-three ring (3.2.1.0 of 3- 2,6) last of the ten Heavenly stems-8-base oxygen-4-methoxybenzaldehyde
-three ring (3.2.1.0 in getting 2,6) decyl alcohol-8-(5.17 gram, 34 millimoles), isovanillin (5.17 grams, 34.0 mmole), triphenyl phosphine (10.7 grams, 40.8 mmoles) and diethylazodicarboxylate's (6.4 milliliters, 40.8 mmoles) are dissolved in 200 milliliters of Si hydrogen Fu Nan And and refluxed together 36 hours.Reaction mixture is cooled to room temperature, with 400 milliliters of ethers and the dilution of 100 ml waters.Water layer and organic layer are separated, and organic layer is with 2 * 100 ml waters, 2 * 0.5NNaoH, and 2 * 100 ml waters, 1 * 100 milliliter of salt solution washing, dried over mgso is filtered, in vacuum concentration.Product flash chromatography (SiO 2, 10% vinyl acetic monomer/hexane) and purifying, suitable part at vacuum concentration, is made 1.28 grams (14%) three ring-aryl aldehyde.
1H NMR（300MHz，CDCl 3）：delta9.8（s，1H），7.43（dd，1H，J＝9Hz，J＝1Hz），7.3（d，1H，J＝1Hz），6.9（d，1H，J＝9Hz），4.3（m，1H），3.9（s，3H），2.4-.9（m，14H）。
Preparation U
1-(3-(dicyclo (2.2.1)-heptan-the 2-yl)-the 4-p-methoxy-phenyl) ethanol-1
Get aldehyde (3 grams, 12.2 mmoles) and be dissolved in 10 milliliters of anhydrous tetrahydro furans, this solution is added in 10 milliliters of tetrahydrofuran solutions of methyl magnesium bromine (15 mmole).Make reaction mixture slowly rise to room temperature and be stirred overnight at room temperature.Reaction suppresses with 10 milliliters of aqueous ammonium chloride solutions, product ethyl acetate extraction 2 times.The organic layer that merges washs with salt solution, and dried over mgso is filtered in vacuum concentration, and the alcohol that makes 2.9 grams (90.7%) is 7: 3 inside/outside mixtures of isomer.
1H NMR（60MHz，CDCl 3）：delta7.8-6.8（m，3H），5.0-4.0（m，2H），4.0（2s，3H），3.0-1.2（m，13H）。
1-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl) ethanol-1-alcohol, from 3-1,2-indane-2-base oxygen-4-methoxybenzaldehyde prepares yield 97.5% with similar approach
1H NMR（60MHz CDCl 3）：delta7.2-6.7（m，7H），5.1（m，1H），4.9（q，1H，J＝6Hz），3.8（s，3H），3.3（m，4H），1.5（d，3H，J＝6Hz）。
Preparation V
Three ring (3.2.1.0 2,6) decyl alcohol-4
Get three ring (3.2.1.0 2,6) decanone-4(1.5 gram, 10 mmoles) be dissolved in 25 milliliters of dehydrated alcohols, handle with sodium borohydride (0.189 gram, 5.0 mmoles).Reaction mixture was stirred 24 hours, and in vacuum concentration, the crude product that obtains is dissolved in ether again.Organic layer 2X water, the washing of 2X salt solution, drying is filtered, and in vacuum concentration, the alcohol that makes 1.47 grams (96.79%) is transparent oil.
1H NMR（300MHz，CDCl 3）：delta4.2（m，1H），2.4-1.2（m，14H）.
13C NMR（75.43MHz，CDCl 3）：delta76.71，43.10，41.75，39.48，34.43，22.32（6 lines）.
Preparation W
1-(3-(dicyclo (2.2.1)-heptan-2-base oxygen)-the 4-p-methoxy-phenyl) ketene
The title compound alcohol (2.9 grams, 11.07 mmoles) of getting preparation U is dissolved in 20 milliliters of acetone, handles with 12.5 milliliters of 1M Jones reagents.Reaction mixture was stirred 2 hours, and water suppresses, product ethyl acetate extraction 3 times.The organic layer water that merges, the salt solution washing, dried over mgso is filtered and in vacuum concentration.Crude product SiO 2Chromatography is made elutriant with 4: 1 hexane/ethyl acetate, obtains 1.5 gram (52.7%) viscous oils, is the methyl ketone mixture of isomers.
1H NMR（60MHz，CDCl 3）：delta7.7-7.3（m，2H），7.2-6.8（m，1H），5.0-4.1（m，1H），4.0（bs，3H），3.0-1.0（m，10H），2.6（s，3H）.
1-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl) ketene, with similar approach from 1-(3-(1,2-indane-2-base oxygen)-4-p-methoxy-phenyl) ethanol-1 preparation, yield 52.1%.
1H NMR（60MHz，CDCl 3）：delta7.6-6.7（m，7H），5.2（m，1H），3.9（s，3H），3.3（m，4H），2.4（s，3H）.
Preparation X
In the 3-(-dicyclo (2.2.1)-heptan-2-base oxygen)-4-p-methoxy-phenyl muriate
With in the 3-(-dicyclo (2.2.1)-heptan-2-base oxygen)-4-methoxyl group benzylalcohol (8.5 grams, 34.3 mmole) and (5.7 milliliters of triethylamines, 41.2 dichloromethane solution mmole) (75 milliliters) is cooled to 0 ℃ and drip Methanesulfonyl chloride (2.9 milliliters, 37.8 mmoles) in this solution.Then reaction mixture was stirred 2 hours, and dilute with water, remove the methylene dichloride phase.Water layer methylene dichloride re-extract with dichloromethane extraction liquid water and the salt solution washing that merges, filters and concentrates in a vacuum with dried over sodium sulfate then, and making 8.0 gram (87.5%) orange oil is the benzyl muriate.
1H NMR（300MHz，CDCl 3）：delta6.8（m，3H），4.5（m，1H），4.35（s，1H），3.8（s，3H），2.6-1.0（m，10H）。
Use similar approach, 3-(1,2-indane-2-base oxygen)-4-methoxy-benzyl muriate, can make from corresponding alcohol.
HRMS molecule measuring definite value: 288.0900(M +)
C 17H 17O 2Cl molecular weight calculated value: 288.0913
Preparation Y
3-(1,2-indane-2-base oxygen)-4-methoxy-benzyl prussiate
Get 3-(1,2-indane-2-base oxygen)-4-methoxy-benzyl muriate (17.7 grams, 61.4 mmoles) is dissolved in 150 milliliters of methyl-sulphoxides and handles (7.9 grams, 121.5 mmoles) with potassium cyanide.Reaction mixture in stirring at room 4.5 hours, is distributed it then between water and vinyl acetic monomer, with 2 parts of water, 2 parts of salt solutions washings through dried over mgso, are filtered, in vacuum concentration.Crude product flash chromatography (SiO 2, 3: 1 hexane/ethyl acetate) purify.Merge suitable part and concentrate in vacuum, making 9.2 gram (53%) light yellow solids is the benzyl prussiate.
1H NMR（CDCl 3，300MHz）：delta7.3-7.2（m，4H），6.9（m，3H），5.22（m，1H），3.9（s，1H），3.75（s，2H），3.5-3.2（m，4H）。
Similarly, in the 3-(-dicyclo (2.2.1)-heptan-2-base oxygen)-4-methoxy-benzyl prussiate, benzyl muriate preparation accordingly, yield 52%.
1H NMR（300MHz，CDCl 3）：delta6.8（m，3H），4.5（m，1H），3.8（s，3H），3.6（s，2H），2.5-1.0（m，10H）。
Preparation Z
3-(dicyclo (2.2.1)-heptan-2-base oxygen)-4-methoxyl group-phenyl aldehyde
(in 7: 3: outer mixture)
Get one of demonstration of isovanillin (50 grams, 0.328 mmole) and be furnished with in the 1 liter round-bottomed flask of splash bar and reflux condensing tube, 500 milliliters of dimethyl formamides reinject.Salt of wormwood (45.3 grams, 0.328 mole) is added in the reaction mixture, be heated to 80 ℃.Add outer-2-bromo norbornane (12.57 restrain, 0.072 mole, 0.219 equivalent) and reaction mixture is heated to 120 ℃ in this temperature and kept 48 hours.Then reaction mixture is cooled in room temperature and impouring 300 ml waters.Water layer washs with 1N sodium hydroxide solution (4 * 100 milliliters), water (3 * 100 milliliters) and saturated nacl aqueous solution (3 * 100 milliliters) with extracted with diethyl ether (3 * 100 milliliters), ether layer.Organic layer filters through anhydrous magnesium sulfate drying, and vacuum concentration makes green/brown oil.With thick product flash chromatography, to purify with vinyl acetic monomer/hexane gradient elution system (10% vinyl acetic monomer/hexane → 20% vinyl acetic monomer/hexane), the white solid that makes 7.76 grams (14.4%) is an aldehyde.
Fusing point: 75.5 ℃-79.5 ℃
Product be inside/outside dicyclo (2.2.1)-heptan-7: 3 mixtures of 2-base ether.
1H-nmr（300 MHzCDCl 3）：delta9.82（s，1H），7.41（m，1H），7.31（d，1H），6.95（d，1H，J＝9Hz），4.6-4.7（m，.7H）[endo]，4.2-4.3（m，.3H）（exo），3.93（s，2.1H）[endo]，3.91（s，.9H）[exo]，2.7-.9（m，10H）.
Following compounds prepares from suitable reactant with similar approach:
Outer-three ring (3.2.1.0 of 3-( 2,6) last of the ten Heavenly stems-4-base oxygen)-the 4-methoxybenzaldehyde, yield 60.2%.
1H NMR（300MHz，CDCl 3）：delta9.8（s，1H），7.4-7.3（m，2H），6.85（m，1H），4.8（m，1H），3.85（s，3H），2.3-3.9（m，14H）.
Preparation AA
In the 3-(-dicyclo (2.2.1)-heptan-2-base oxygen)-the 4-methoxybenzaldehyde
In 4-bromo-2-(-dicyclo (2.2.1)-heptan-2-base oxygen)-4-anisole (5.14 grams, 17.4 mmoles) is dissolved in 150 milliliters of exsiccant tetrahydrofuran (THF)s.A little solution are cooled to-78 ℃, and drip the pentane solution of 20.5 milliliters of 1.7 moles of four-butyllithiums (34.8 mmole).This solution was stirred 1.5 hours at-78 ℃, use N then, 30 milliliters of tetrahydrofuran solutions of dinethylformamide (13.2 milliliters, 170 mmoles) are handled.Reaction mixture was stirred 1.5 hours at-78 ℃, slowly rise to room temperature then.Reaction mixture is diluted with 300 milliliters of ether, with 3 * 200 ml waters and 1 * 100 milliliter of salt solution washing.Organic layer filters through anhydrous magnesium sulfate drying, and in vacuum concentration, making 4.04 gram (95%) white powders is phenyl aldehyde, fusing point 87-88 ℃.
1H NMR（300MHz，CDCl 3）：delta9.82（s，1H），7.4（dd，1H，J＝9，J＝1），7.3（d，1H，J＝1Hz），6.9（d，J＝9Hz），4.65（m，1H），3.93（s，1H），2.65（m，1H），2.3（m，1H），2.15（m，1H），2.05（m，1H），1.6（m，1H），1.4（m，4H），1.08（m，1H）.
Press aforesaid operations, following benzaldehyde derivative can be from corresponding bromo-reaction thing to: 3-(in-three ring (3.2.1.0 2,6) last of the ten Heavenly stems-8-base oxygen)-the 4-methoxybenzaldehyde, yield 64%.
1H NMR（300MHz，CDCl 3）：delta9.8（s，1H），7.5-7.3（m，2H），6.95（m，1H），4.7（m，1H），3.97（s，3H），2.8-1.0（m，14H）。
In the 3-(-benzo dicyclo (2.2.1)-heptan-2-base oxygen)-the 4-methoxybenzaldehyde, yield 51.8%.
1H NMR（300MHz，CDCl 3）：delta9.6（s，1H），7.3-7.2（m，2H），7.1-6.9（m，4H），6.7（m，1H），5.0（m，1H），3.6（m，1H），3.55（s，3H），3.25（m，1H），2.2（m，1H），1.8（m，1H），1.65（m，1H），1.05（m，1H）.
Preparation BB
Outside the 3-(-dicyclo (2.2.2)-Xin-2-base oxygen)-the 4-methoxybenzaldehyde
Get dicyclo (2.2.2)-sec-n-octyl alcohol (5.00 grams, 40 mmoles), isovanillin (6.09 grams, 40 mmoles) and triphenylphosphine (13.1 grams, 50 mmoles) are dissolved in anhydrous tetrahydro furan.In this reaction-ure mixture, drip diethylazodicarboxylate's (8.71 grams, 50 mmoles).Reaction mixture in stirring at room 1 hour, was refluxed 80 hours then.With the reaction mixture cooling, in vacuum concentration, resistates washs with 3 * 150 milliliters of ethers, separates required product from triphenyl phosphine oxide.The ether layer that merges is with 2 * 100 ml waters, 2 * 100 milliliters of 2N NaoH solution, and 2 * 100 ml waters and 2 * 100 milliliters of salt solutions wash.The organic layer drying is filtered, in vacuum concentration.The quick silica gel of compound (32-80 order) chromatogram is purified, with 20% vinyl acetic monomer/hexane as elutriant.Suitable part in vacuum concentration, is made the product of 3.32 gram (32%) viscous oils.
1H NMR（250MHz，CDCl 3）：delta7.4（dd，1H，J＝8.5Hz，J＝1.5Hz），7.35（d，1H，J＝1.5Hz），6.95（d，1H，J＝8.5Hz），4.52（m，1H），3.91（s，3H），2.2-1.3（m，12H）.
13C NMR（63MHz，CDCl 3）：delta190.9，155.7，147.9，129.97，126.2，112.6，110.9，77.5，56.1，34.74，28.18，25.25，24.55，23.29，22.78，19.09（16 lines）。
Preparation CC
Outside the 3-(-dicyclo (3.2.1) suffering-2-base oxygen)-the 4-methoxybenzaldehyde
Get cis-dicyclo (3.2.1)-3-octanol (1.90 grams, 0.015 mole), triphenyl phosphine (4.72 grams, 0.018 mole), isovanillin (2.73 grams, 0.018 mole) and diethylazodicarboxylate's (2.83 milliliters, 0.018 mole) are dissolved in 75 milliliters of anhydrous tetrahydro furans.With reaction mixture refluxed 15 hours, cooling was diluted with 50 milliliters of ether and 50 ml waters.Separate water layer, with 2 * 25 milliliters of ether extractions.The organic layer that merges is with 2 * 25 ml waters, 2 * 25 milliliters of 1N NaOH solution, and 2 * 25 ml waters, 2 * 25 milliliters of 3MpH7 phosphate buffered saline buffers and 2 * 25 milliliters of salt solutions wash.Organic layer is through dried over mgso, in vacuum concentration to 50 milliliter, and with 250 milliliters of hexanes dilutions, filters, and removes the triphenyl phosphine oxide precipitation.Repeat this operation three times, remove residual triphenyl phosphine oxide.The organic layer that obtains filters through dried over mgso, and in vacuum concentration, making 1.68 gram (43%) transparent oil is aryl ethers.
1H NMR（300MHz，CDCl 3）：delta10.01（s，1H），7.3-7.1（m，2H），6.8（m，1H），4.4（m，1H），3.78（s，3H），2.3-1.3（m，12H）。
Preparation DD
-three ring (3.3.1.1 in the 3-( 3,7) last of the ten Heavenly stems-2-base oxygen)-the 4-methoxybenzaldehyde
Get isovanillin (10.75 grams, 70.72 mmoles), 2-adamantanol (8.6 grams, 56.5 mmole), triphenyl phosphine (18.53 grams, 70.72 mmoles) and diethylazodicarboxylate's 280 milliliters of tetrahydrofuran (THF)s of (11.12 milliliters, 70.72 mmoles) solution and temperature rising reflux 24 hours.Reaction mixture is cooled off, with 500 milliliters of ether dilutions, with 2 * 100 ml waters, 2 * 100 milliliters of 0.5N NaoH solution, 2 * 100 ml waters, 1 * 100 milliliter of 3M pH7 phosphate buffer, 1 * 100 milliliter of salt solution washing, with organic layer in vacuum concentration to 100 milliliter, with 500 milliliters of hexanes dilutions to measure triphenyl phosphine oxide.Solution through dried over mgso, is filtered, and in vacuum concentration, pure aldehyde separates with the bisulfite salt formation/release steps of standard, and making 5.29 gram (33%) viscous oils is aldehyde.
1H NMR（300MHz，CDCl 3）：delta7.4（m，2H），6.95（m，1H），4.52（bs，1H），3.92（s，3H），2.3-1.4（m，14H）。
China's invention 899 is flat
103201-225

Claims (15)

1、一种制备下式(Ⅰ-q)化合物的方法，1. A method for preparing compounds of the following formula (I-q),
Figure 87103225_IMG2
Figure 87103225_IMG2
 式中R1是具有7-11个碳原子的多环烷基；和In the formula, R is a polycycloalkyl group with 7-11 carbon atoms; and R2是甲基或乙基，此法包括将式(Ⅻ)的化合物与脲，在强酸存在下，在反应-惰性的溶剂中进行反应，R 2 is methyl or ethyl, this method comprises with formula (XII) compound and urea, in the presence of strong acid, react in reaction-inert solvent,
Figure 87103225_IMG3
Figure 87103225_IMG3
 式中R1和R2的定义如上所述。The definitions of R1 and R2 in the formula are as above. 2、按权利要求1所述的方法，其中R1是双环烷基;和R2是甲基或乙基。2. The method of claim 1, wherein R1 is bicycloalkyl; and R2 is methyl or ethyl. 3、按权利要求2所述的方法，其中R1是双环〔2.2.1〕庚-2-基或1，2-二氢化茚-2-基和R2是甲基。3. A process as claimed in claim 2, wherein R1 is bicyclo[2.2.1]hept-2-yl or indan-2-yl and R2 is methyl. 4、一种制备下式（Ⅰ-i）化合物的方法，4. A process for the preparation of compounds of the following formula (I-i), 式中R1是具有7-11个碳原子的多环烷基;和In the formula, R is a polycycloalkyl group with 7-11 carbon atoms; and R2是甲基或乙基，此法包括将具有下式（Ⅰ-g或Ⅰ-h）化合物，在有氢气和甲基化催化剂存在下，在反应-惰性的溶剂中还原;和如需要的话，可以制成所述化合物的药物上可接受的酸加成盐。 R2 is methyl or ethyl, the method comprising reducing a compound of the following formula (I-g or I-h) in a reaction-inert solvent in the presence of hydrogen and a methylation catalyst; and If so, pharmaceutically acceptable acid addition salts of the compounds can be prepared.
Figure 87103225_IMG5
Figure 87103225_IMG5
 5、按权利要求4所述方法，其中R1是双环烷基和R2是甲基。5. The method of claim 4, wherein R1 is bicycloalkyl and R2 is methyl. 6、按权利要求5所述方法，其中R1是双〔2.2.1〕庚-2-基或1，2-二氢化茚-2-基。6. A process as claimed in claim 5, wherein R1 is bis[2.2.1]hept-2-yl or indan-2-yl. 7、一种制备下式（Ⅰ-i）化合物的方法，7. A process for the preparation of compounds of the following formula (I-i),
Figure 87103225_IMG6
Figure 87103225_IMG6
 式中R1是具有7-11碳原子的多环烷基;和In the formula, R is a polycycloalkyl group with 7-11 carbon atoms; and R2是甲基或乙基，此法包括将具有下式化合物，在环境温度及四醋酸铅的存在下，于反应-惰性的溶剂中进行环化，R 2 is methyl or ethyl, and this method comprises will have following formula compound, under ambient temperature and the presence of lead tetraacetate, carry out cyclization in reaction-inert solvent, 式中R和R的定义与上述相同。The definitions of R and R in the formula are the same as above. 8、按权利要求7所述的方法，其中R1是双环烷基;和R2是甲基或乙基。8. The method of claim 7, wherein R1 is bicycloalkyl; and R2 is methyl or ethyl. 9、按权利要求8所述的方法，其中R1是双环〔2.2.1〕庚-2-基或1，2-二氢化茚-2-基;和R2是甲基。9. A process as claimed in claim 8, wherein R1 is bicyclo[2.2.1]hept-2-yl or indan-2-yl; and R2 is methyl. 10、一种制备下式（Ⅰ-a）化合物的方法，10. A process for the preparation of compounds of the following formula (I-a),
Figure 87103225_IMG8
Figure 87103225_IMG8
 式中R1是具有7-11个碳原子的多环烷基;In the formula, R 1 is a polycyclic alkyl group with 7-11 carbon atoms; R2是甲基或乙基;R 2 is methyl or ethyl; R3是氢，（C1-5）烷基，（C2-5）链烯基，苄基或苯乙基;和 R3 is hydrogen, ( C1-5 ) alkyl, ( C2-5 ) alkenyl, benzyl or phenethyl; and R4是氢，（C1-5）烷基，选择性地任意具有碱基的（C1-5）链烷酰基，或苯甲酰基;R 4 is hydrogen, (C 1-5 )alkyl, optionally (C 1-5 )alkanoyl optionally with a base, or benzoyl; 此法包括将下式（Ⅴ）化合物，在N，N′-羰基二咪唑或1，1-羰基-1，2，4-三唑存在下，于20-65℃温度下，在反应一惰性的溶剂中进行环化，This method includes the compound of the following formula (V), in the presence of N, N'-carbonyldiimidazole or 1,1-carbonyl-1,2,4-triazole, at a temperature of 20-65 ° C, in a reaction-inert cyclization in a solvent,
Figure 87103225_IMG9
Figure 87103225_IMG9
 式中R1，R2，R3和R4的定义如上所述;和，如需要的话，将其中R3和R4至少一个是氢的式（Ⅴ）的化合物进行酰化或烷基化。wherein R 1 , R 2 , R 3 and R 4 are as defined above; and, if desired, acylation or alkylation of a compound of formula (V) wherein at least one of R 3 and R 4 is hydrogen . 11、按权利要求10所述的方法，其中R1是双环〔2.2.1〕庚-2-基或1，2-二氢化茚-2-基;R2和R3各是甲基;和R4是氢。11. A process according to claim 10, wherein R1 is bicyclo[2.2.1]hept-2-yl or 1,2-indan-2-yl; R2 and R3 are each methyl; and R4 is hydrogen. 12、一种制备下式化合物的方法，12. A process for preparing a compound of the formula,
Figure 87103225_IMG10
Figure 87103225_IMG10
 式中R1是具有7-11个碳原子的多环烷基;和R2是甲基或乙基，此法包括将具有下式化合物在反应-惰性的溶剂中，进行加热脱羧，In the formula, R 1 is a polycyclic alkyl group with 7-11 carbon atoms; and R 2 is a methyl group or an ethyl group, and this method includes the compound of the following formula in a reaction-inert solvent, carrying out decarboxylation by heating,
Figure 87103225_IMG11
Figure 87103225_IMG11
 式中R1和R2的定义如上所述和R是（C1-5）烷基。wherein R 1 and R 2 are as defined above and R is (C 1-5 )alkyl. 13、一种制备下式（Ⅰ-O）化合物的方法，13. A process for the preparation of compounds of the following formula (I-O),
Figure 87103225_IMG12
Figure 87103225_IMG12
 式中R1是具他7-11个碳原子的多环烷基;和R2是甲基或乙基;In the formula, R 1 is a polycyclic alkyl group with other 7-11 carbon atoms; and R 2 is methyl or ethyl; 此法包括将下式（Ⅻ）化合物与2-氨基咪唑，在矿物酸存在下，在反应-惰性的溶剂中进行反应，This method comprises with following formula (XII) compound and 2-aminoimidazoles, in the presence of mineral acid, react in reaction-inert solvent,
Figure 87103225_IMG13
Figure 87103225_IMG13
 式中R1和R2的定义如上所述。The definitions of R1 and R2 in the formula are as above. 14、按权利要求13所述的方法，其中R1是双环烷基;和R2是甲基或乙基。14. The method of claim 13, wherein R1 is bicycloalkyl; and R2 is methyl or ethyl. 15、一种制备下式（Ⅰ-n）化合物的方法，15. A process for the preparation of compounds of the following formula (I-n),
Figure 87103225_IMG14
Figure 87103225_IMG14
 式中R1是具有7-11个碳原子的多环烷基;和R2是甲基或乙基，此法包括将式（ⅩⅥ）的化合物与3-氨基吡唑，在矿物酸存在下，于反应-惰性的溶剂中进行反应，In the formula, R1 is a polycyclic alkyl group having 7-11 carbon atoms; and R2 is methyl or ethyl. This method comprises the compound of formula (XVI) with 3-aminopyrazole, in the presence of mineral acid , react in a reaction-inert solvent, 其中R1和R2的定义如上所述。wherein R 1 and R 2 are as defined above.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102731411A (en) * 2012-06-15 2012-10-17 湖南大学 Preparation of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone and application of same as antidepressant drug

Families Citing this family (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8610531D0 (en) * 1986-04-30 1986-06-04 Fbc Ltd Herbicides
DE3823299A1 (en) * 1988-07-07 1990-01-11 Schering Ag SUBSTITUTED PHENYL-PYRROLIDIN-2-ONE, -OXAZOLIDIN-2-ONE AND -IMIDAZOLIDIN-2-ONE, THEIR PRODUCTION AND USE IN MEDICINAL PRODUCTS
WO1991007501A1 (en) * 1989-11-13 1991-05-30 Pfizer Inc. Enzymatic resolution of endo-bicyclo[2.2.1]heptan-2-ol and derived pharmaceutical agents
WO1991007177A1 (en) * 1989-11-13 1991-05-30 Pfizer Inc. Pyrimidone derivatives and analogs in the treatment of asthma or certain skin disorders
ATE161720T1 (en) * 1990-08-03 1998-01-15 Smithkline Beecham Corp TNF INHIBITORS
US5124455A (en) * 1990-08-08 1992-06-23 American Home Products Corporation Oxime-carbamates and oxime-carbonates as bronchodilators and anti-inflammatory agents
WO1992007567A1 (en) * 1990-11-06 1992-05-14 Smithkline Beecham Corporation Imidazolidinone compounds
US5547979A (en) * 1992-03-30 1996-08-20 Smithkline Beecham TNF inhibition
US5395935A (en) * 1992-05-08 1995-03-07 Pfizer Inc. Endo-bicyclo[2.2.1]heptan-2-ol and derived pharmaceutical agents
GB9212673D0 (en) * 1992-06-15 1992-07-29 Celltech Ltd Chemical compounds
GB9222253D0 (en) * 1992-10-23 1992-12-09 Celltech Ltd Chemical compounds
US5814651A (en) * 1992-12-02 1998-09-29 Pfizer Inc. Catechol diethers as selective PDEIV inhibitors
CA2400368A1 (en) * 1992-12-02 1994-06-09 Allen J. Duplantier Catechol diethers as selective pde iv inhibitors
GB9226830D0 (en) * 1992-12-23 1993-02-17 Celltech Ltd Chemical compounds
US5622977A (en) * 1992-12-23 1997-04-22 Celltech Therapeutics Limited Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same
GB9304919D0 (en) * 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
GB9304920D0 (en) * 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
US5665754A (en) * 1993-09-20 1997-09-09 Glaxo Wellcome Inc. Substituted pyrrolidines
US5502072A (en) * 1993-11-26 1996-03-26 Pfizer Inc. Substituted oxindoles
EP0730587B1 (en) * 1993-11-26 1999-12-08 Pfizer Inc. 3-phenyl-2-isoxazolines as antiinflammatory agents
EP0738268B1 (en) * 1993-12-22 2004-03-03 Celltech R&D Limited Trisubstituted phenyl derivatives, processes for their preparation and their use as phosphodiesterase (type iv) inhibitors
GB9326173D0 (en) * 1993-12-22 1994-02-23 Celltech Ltd Chemical compounds and process
US5696141A (en) * 1994-03-09 1997-12-09 Pfizer Inc. Isoxazoline compounds as 5-lipoxygenase inhibitors
DK0749428T3 (en) * 1994-03-09 1998-11-16 Pfizer Isooxazoline Compounds as Inhibitors of TNF Release
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
US5786354A (en) * 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
GB9412571D0 (en) 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
GB9412573D0 (en) * 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
GB9412672D0 (en) * 1994-06-23 1994-08-10 Celltech Ltd Chemical compounds
US5922751A (en) * 1994-06-24 1999-07-13 Euro-Celtique, S.A. Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same
KR100234602B1 (en) 1994-08-05 1999-12-15 디. 제이. 우드, 스피겔 알렌 제이 5- (3- (exo-bicyclo (2.2.1) hept-2-yloxy) -4-methoxyphenyl) -3,4,5,6-tetrahydropyrimidin-2 (1H) -one Synthesis Method and Intermediates in It
GB9523675D0 (en) * 1995-11-20 1996-01-24 Celltech Therapeutics Ltd Chemical compounds
GB9526246D0 (en) * 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
GB9526245D0 (en) * 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
DE19617864A1 (en) * 1996-04-23 1997-10-30 Schering Ag New chiral phenyldihydrofuranones
GB9608435D0 (en) * 1996-04-24 1996-06-26 Celltech Therapeutics Ltd Chemical compounds
US6294541B1 (en) 1996-06-06 2001-09-25 Euro-Celtique S.A. Purine derivatives having phosphodiesterase IV inhibition activity
WO1998004534A1 (en) 1996-07-31 1998-02-05 Nikken Chemicals Co., Ltd. 6-phenyltetrahydro-1,3-oxazin-2-one derivatives and medicinal compositions containing the same
EP0924204A4 (en) 1996-08-27 2002-10-23 Nikken Chemicals Co Ltd 2-phenylmorpholin-5-one derivatives and pharmaceutical composition comprising the same
GB9619284D0 (en) * 1996-09-16 1996-10-30 Celltech Therapeutics Ltd Chemical compounds
US5744473A (en) * 1996-09-16 1998-04-28 Euro-Celtique, S.A. PDE IV inhibitors: "bis-compounds"
GB9622363D0 (en) 1996-10-28 1997-01-08 Celltech Therapeutics Ltd Chemical compounds
GB9625184D0 (en) * 1996-12-04 1997-01-22 Celltech Therapeutics Ltd Chemical compounds
WO1998028281A1 (en) * 1996-12-23 1998-07-02 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives, their preparation and their use as protein tyrosine kinase inhibitors
GB9705361D0 (en) * 1997-03-14 1997-04-30 Celltech Therapeutics Ltd Chemical compounds
GB9713087D0 (en) * 1997-06-20 1997-08-27 Celltech Therapeutics Ltd Chemical compounds
DE19882893T1 (en) 1997-12-12 2001-02-22 Euro Celtique Sa Preparation of 3-substituted adenines
US6319928B1 (en) 1998-11-30 2001-11-20 Euro-Celtique, S.A. Purine derivatives having phosphodiesterase IV inhibition activity
AR029347A1 (en) 1999-04-02 2003-06-25 Euro Celtique Sa ADENINE COMPOUND, ISOGNANINE COMPOUND AND 2,6-DITIOXANTINE AS A PRECURSOR OF THE SAME, USE OF SUCH COMPOUNDS TO PREPARE A PHARMACEUTICAL COMPOSITION AND SUCH PHARMACEUTICAL COMPOSITION
GB9914258D0 (en) 1999-06-18 1999-08-18 Celltech Therapeutics Ltd Chemical compounds
GB9924862D0 (en) 1999-10-20 1999-12-22 Celltech Therapeutics Ltd Chemical compounds
ATE420077T1 (en) 2001-05-29 2009-01-15 Bayer Schering Pharma Ag CDK INHIBITORY PYRIMIDINES, THEIR PREPARATION AND USE AS MEDICINAL PRODUCTS
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
KR100753017B1 (en) * 2006-05-25 2007-08-30 한국화학연구원 For the treatment of brain diseases such as arthritis, atopic dermatitis, cancers including leukemia and Alzheimer's, depression or memory loss, including 7- (3,4-diakoxyphenyl) -pyrazolo [1,5-a] pyrimidine compounds, and Pharmaceutical Compositions for Prevention
CA2688161C (en) 2007-06-04 2020-10-20 Kunwar Shailubhai Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
ES2522968T3 (en) 2008-06-04 2014-11-19 Synergy Pharmaceuticals Inc. Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2010009319A2 (en) 2008-07-16 2010-01-21 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
JP2011144169A (en) * 2009-12-18 2011-07-28 Ishihara Sangyo Kaisha Ltd Imidazopyrimidine derivative or salt thereof, and noxious organism control agent comprising the same
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
CA2828346C (en) 2011-03-01 2021-01-26 Synergy Pharmaceuticals Inc. Process of preparing guanylate cyclase c agonists
JP6499591B2 (en) 2013-02-25 2019-04-10 シナジー ファーマシューティカルズ インコーポレイテッド Guanylate cyclase receptor agonists for use in colon lavage
EP2968439A2 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
CA2905438A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
KR102272746B1 (en) 2013-06-05 2021-07-08 보슈 헬스 아일랜드 리미티드 Ultra-pure agonists of guanylate cyclase c, method of making and using same
IL280864B2 (en) 2013-08-09 2024-03-01 Ardelyx Inc Compounds and methods for inhibiting phosphate transport
EP3972599A1 (en) 2019-05-21 2022-03-30 Ardelyx, Inc. Combination for lowering serum phosphate in a patient

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1451154A (en) * 1959-06-22 1966-01-07 Guy Hue Lab New pyrazole derivatives and their preparation process
NL136620C (en) * 1963-04-30
US3923833A (en) * 1968-05-01 1975-12-02 Hoffmann La Roche N-{8 (1-cyano-2-phenyl)ethyl{9 carbamates
BE759176A (en) * 1969-11-20 1971-05-19 Sandoz Sa PYRIMIDINE DERIVATIVES, THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE DERIVES
US3636039A (en) * 1970-02-24 1972-01-18 Hoffmann La Roche Substituted benzylimidazolidinones
DE2413935A1 (en) * 1974-03-20 1975-10-16 Schering Ag 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE
US4193926A (en) * 1974-03-20 1980-03-18 Schering Aktiengesellschaft 4-(Polyalkoxy phenyl)-2-pyrrolidones
IE40911B1 (en) * 1974-04-11 1979-09-12 Schering Ag Imidazole derivatives and process for their manufacture
DE2541855A1 (en) * 1975-09-18 1977-03-31 Schering Ag 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE II
SU888821A3 (en) * 1976-12-03 1981-12-07 Шеринг Аг (Инофирма) Method of preparing 5-(substituted phehyl)-oxazolidinones or their sulphur-containing analogs
HU179019B (en) * 1978-11-01 1982-08-28 Gyogyszekutato Intezet Process for preparing 4-//3,4-dialkoxy-phenyl/-alkyl/- 2imidazolidinone derivatives
US4261995A (en) * 1979-08-31 1981-04-14 Syntex (U.S.A.) Inc. 4-Phenyl-and 5-phenyl-1,4,5,6-tetrahydropyrimidine derivatives
DE3130633A1 (en) * 1981-08-01 1983-02-17 Basf Ag, 6700 Ludwigshafen 7-AMINO-AZOLO (1,5-A) PYRIMIDINE AND FUNGICIDES CONTAINING THEM
DE3315797A1 (en) * 1983-04-30 1984-10-31 Beiersdorf Ag, 2000 Hamburg SUBSTITUTED PHENYL-2- (1H) -PYRIMIDINONE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE, AND PREPARATIONS CONTAINING THESE COMPOUNDS
JPS6019789A (en) * 1983-07-12 1985-01-31 Kyorin Pharmaceut Co Ltd Imidazo(1,5-a)pyrimidine derivative

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102731411A (en) * 2012-06-15 2012-10-17 湖南大学 Preparation of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone and application of same as antidepressant drug
CN102731411B (en) * 2012-06-15 2014-10-22 湖南大学 Preparation of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone and application of same as antidepressant drug

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